JP2001526268A - Nitrogen-containing heterocyclic aromatic compounds having ortho-substituted P1 as factor Xa inhibitors - Google Patents

Abstract

(57) Abstract The present application relates to a nitrogen-containing heterocyclic aromatic compound having an ortho-substituted P1 group represented by the formula (I) and a derivative thereof, or a pharmaceutically acceptable salt thereof or a pro-form thereof. Describe the drug. Wherein J is N or NH, D is ortho substituted for G on E, and can be CH ₂ NH ₂ . These are useful as factor Xa inhibitors. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention generally relates to nitrogen-containing heteroaromatic compounds having an ortho-substituted P1 group, which are inhibitors of trypsin-like serine protease enzymes, particularly factor Xa, and pharmaceuticals containing the same. Compositions and methods of using them as anticoagulants for the treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION International patent application WO 95/18111 is directed to fibrinogen receptor antagonists, which contain basic and acidic ends of the formula:

[0003]

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In the above formula, R ¹ represents a basic end, U is an alkylene or a heteroatom linker, V may be a heterocycle, and the right part of the molecule represents an acidic end. The compounds of the present invention do not contain the acidic or basic ends of WO 95/18111.

In US Pat. No. 5,463,071, Himmelsbach et al. Describe a cell aggregation inhibitor which is a 5-membered heterocycle of the formula:

[0006]

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In the above formula, the heterocyclic ring may be an aromatic ring, and the ABC— and FED— groups are attached to a cyclic system. ABC- can be a wide variety of substituents, including basic groups attached to an aromatic ring. However, the FED- group appears to be an acidic functional group different from the present invention. Furthermore, the use of these compounds as factor Xa inhibitors is not discussed.

[0008] Baker et al. In US Pat. No. 5,317,103 discuss 5-HT ₁ agonists, which are indole-substituted 5-membered heteroaromatic compounds of the formula:

[0009]

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In the above formula, R ¹ may be pyrrolidine or piperidine, and A may be a basic group including amino and amidino. However, Baker et al. Do not indicate that A can be a substituted cyclic system as included in the heteroaromatic compounds of the present invention.

[0011] Baker et al. Discuss in international patent application WO 94/02477 a 5-HT ₁ agonist that is an imidazole, triazole, or tetrazole of the formula:

[0012]

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In the above formula, R ¹ represents a nitrogen-containing cyclic system or a nitrogen-substituted cyclobutane, and A may be a basic group including amino and amidino. However, Bake
do not indicate that A can be a substituted cyclic system as included in the heteroaromatic compounds of the present invention.

Illig et al. In WO 97/47299 exemplify amidino and guadinino heterocyclic protease inhibitors of the formula:

[0015]

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Wherein R ¹ is a substituted aryl group, Z is a two carbon linker having at least one heteroatom, X is a heterocyclic group, Y is an optional linker, W is an amidino or guanidino-containing group. Such compounds are not considered to be part of the present invention.

Jackson et al. In WO 97/32583 describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula:

[0018]

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In the formula, R ¹ is various heteroaryl groups, R ⁴ is phenyl, naphthyl or heteroaryl group, and R ² is various groups. Jackson et al. Do not teach inhibitors of factor Xa. Further, Jackson et al. Imidazoles are not considered to be part of the present invention.

Activated factor Xa, whose primary practical role is the production of thrombin by the restricted proteolysis of prothrombin, plays a central role in connecting the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. is occupying. The production of thrombin, the final serine protease in the pathway that produces fibrin clots, from its precursors is amplified by the formation of prothrombinase complexes (factor Xa, factor V, Ca ²⁺ and phospholipids). One mole of Factor Xa is calculated to be capable of producing 138 moles of thrombin (Elodi, S. Varadi,
K. : Optimization of conditions fort
he catalytic effect of the factor IX
a-factor VIII Complex: Probable role
of the complex in the amplification
of blood coagulation. Thromb. Res. 197
9, 15, 617-629), therefore, inhibition of factor Xa may be more effective in blocking the blood coagulation system than inactivating thrombin.

Thus, there is a need for effective and specific factor Xa inhibitors as potentially valuable therapeutics for the treatment of thromboembolic disorders. Therefore, the discovery of new Xa inhibitors is desired.

SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide an ortho-
An object of the present invention is to provide a novel nitrogen-containing heterocyclic aromatic compound having a substituted P1 group, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Another object of the present invention is to provide a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof or a prodrug thereof. And to provide a pharmaceutical composition comprising:

Another object of the present invention is to provide a therapeutically effective amount of a compound of the present invention, or at least one pharmaceutically acceptable salt or prodrug thereof, for the treatment of a thromboembolic disease. And a method for treating a thromboembolic disease, which comprises administering to a host.

These and other objects, which will be evident in the following detailed description, are intended to provide the compounds of formula (I)

[0026]

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Alternatively, a pharmaceutically acceptable salt thereof or a prodrug thereof is an effective Xa
It has been achieved by discovering that it is a factor inhibitor. In the above formula, A
, B, D, E, G, J, M, R ^1a , R ^1b , and s are defined below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I

[0029]

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Or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Wherein ring M contains, in addition to J, 0-3 N atoms, provided that M is 2 N atoms
When containing^1bIs absent and if M contains three N atoms, R^1a And R^1bIs absent; J is N or NH; D is CN, C (= NR⁸) NR⁷R⁹, NHC (= NR⁸) NR⁷R⁹, NR⁸CH (= NR⁷), C (O) NR⁷R⁸, And (CR⁸R⁹)_tNR⁷R⁸Selected from
With the proviso that D is substituted ortho to G on E; E is phenyl, pyridyl, pyrimidyl, pyrazinyl substituted with 1-2 R
R is H, Cl, F, Br, I, (CH_Two)_tOR^Three, C_{1 ~ Four}Alkyl, OCF_Three , CF_Three, C (O) NR⁷R⁸, And (CR⁸R⁹)_tNR⁷R⁸G is absent or NHCH_Two, OCH_Two, And SCH_TwoWherein s is 0, G is attached to a carbon atom on ring M; Z is C_{1 ~ Four}Alkylene, (CH_Two)_rO (CH_Two)_r, (CH_Two)_rNR^Three(CH_Two )_r, (CH_Two)_rC (O) (CH_Two)_r, (CH_Two)_rC (O) O (CH_Two)_r, (CH_Two)_rOC (O) (CH_Two)_r, (CH_Two)_rC (O) NR^Three(CH_Two)_r, (CH_Two) _r NR^ThreeC (O) (CH_Two)_r, (CH_Two)_rOC (O) O (CH_Two)_r, (CH_Two)_rO
C (O) NR^Three(CH_Two)_r, (CH_Two)_rNR^ThreeC (O) O (CH_Two)_r, (CH_Two)_r NR^ThreeC (O) NR^Three(CH_Two)_r, (CH_Two)_rS (O)_p(CH_Two)_r, (CH_Two)_r SO_TwoNR^Three(CH_Two)_r, (CH_Two)_rNR^ThreeSO_Two(CH_Two)_r, And (CH_Two)_rN
R^ThreeSO_TwoNR^Three(CH_Two)_rWherein Z is a ring M or a group A and N—N, N—O, N—S, NCH_TwoN, NCH_TwoO or NCH_TwoDoes not form an S bond; R^1aAnd R^1bAre independently absent or-(CH_Two)_r-R^{1 '}, -CH = CH-R^{1 '}, NCH_TwoR^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, NH (CH_Two)_Two (CH_Two)_tR^{1 '}, O (CH_Two)_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two )_tR^{1 '}Or R^1aAnd R^1bAre bonded to adjacent carbon atoms when they are
Together with the joining atoms, from 0 to 2 R^Four5-8 membered saturated, containing 0-2 heteroatoms selected from the group consisting of N, O, and S 1,
Forming a partially saturated or unsaturated ring;^{1 '}Is H, C_{1 ~ Three}Alkyl, F, Cl, Br, I, -CN, -CHO, (CF_Two)_rCF_Three, (CH_Two)_rOR^Two, NR^TwoR^2a, C (O) R^2c, OC (O) R^Two,
(CF_Two)_rCO_TwoR^2c, S (O)_pR^2b, NR^Two(CH_Two)_rOR^Two, CH (= NR^2c ) NR^TwoR^2a, NR^TwoC (O) R^2b, NR^TwoC (O) NHR^2b, NR^TwoC (O)_TwoR^{Two a} , OC (O) NR^2aR^2b, C (O) NR^TwoR^2a, C (O) NR^Two(CH_Two)_rOR^Two , SO_TwoNR^TwoR^2a, NR^TwoSO_TwoR^2b, 0-2 R^FourC substituted with_{Three ~ 6}A carboxylic acid residue and 1 to 4 hetero atoms selected from the group consisting of N, O and S
Containing 0 to 2 R^FourR is selected from a 5- to 10-membered heterocyclic ring system substituted with^{1 "}Is H, CH (CH_TwoOR^Two)_Two, C (O) R^2c, C (O) NR^TwoR^2a, S (O) R^2b, S (O)_TwoR^2bAnd SO_TwoNR^TwoR^2aSelected from; R^TwoIs, in each case, H, CF_Three, C_{1 ~ 6}Alkyl, benzyl, 0-2 R ^4b C substituted with_{Three ~ 6}From the group consisting of carboxylic acid residues and N, O and S
0 to 2 R containing 1 to 4 heteroatoms selected^4bReplaced with 5
R is selected from a 6-membered heterocyclic ring system; R^2aIs, in each case, H, CF_Three, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}A group consisting of carboxylic acid residues and N, O and S
0 to 2 R containing 1 to 4 heteroatoms selected from^4bReplaced by
R is selected from a 5- to 6-membered heterocyclic ring system; R^2bIs, in each case, CF_Three, C_{1 ~ Four}Alkoxy, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}Carboxylic acid residues, and N, O, and
0 to 2 R containing 1 to 4 heteroatoms selected from the group consisting of S^4b R is selected from a 5-6 membered heterocyclic ring substituted with^2cIs, in each case, CF_Three, OH, C_{1 ~ Four}Alkoxy, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}Carboxylic acid residues, and N, O,
0 to 2 containing 1 to 4 heteroatoms selected from the group consisting of
R^4bR is selected from a 5-6 membered heterocyclic ring system;^TwoAnd R^2aIs bonded to and contains 0 to 1 heteroatoms containing 0 to 1 heteroatoms selected from the group consisting of N, O, and S;^4bReplaced by 5 or
Selected from 6 membered saturated, partially saturated or unsaturated rings;^TwoAnd R^2aContains 0 to 1 heteroatoms selected from the group consisting of N, O, and S, which are bonded together with the atoms to which they are bonded.
0 to 2 R^4b5 or 6 membered saturated, partially saturated or unsaturated,
Forming a saturated ring; R^ThreeIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3aIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3bIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3cIs in each case C_{1 ~ Four}A is 0 to 2 R^FourC substituted with_{Three ~ Ten}Carboxylic acid residues and N, O, and
And 2 containing from 1 to 4 heteroatoms selected from the group consisting of
R^FourB is XY, NR selected from a 5-10 membered heterocyclic ring substituted with^TwoR^2a, C (= NR^Two) NR^TwoR^2a, NR^TwoC (= NR^Two) NR^TwoR^2a, 0-2 R^4aC substituted with_{Three ~ Ten}Carboxylic acid residues and N, O
And 0 to 2 containing 1 to 4 heteroatoms selected from the group consisting of
R^4aX is selected from the group consisting of a 5-10 membered heterocyclic ring substituted with_{1 ~ Four}Alkylene, -CR^Two(CR^TwoR^2b) (CH_Two)_t-, -C (O)-
, -C (= NR^{1 "})-, -CR^Two(NR^{1 "}R^Two)-, -CR^Two(OR^Two)-, -C
R^Two(SR^Two)-, -C (O) CR^TwoR^2a-, -CR^TwoR^2aC (O), -S (O)_p -, -S (O)_pCR^TwoR^2a-, -CR^TwoR^2aS (O)_p-, -S (O)_TwoNR^Two−,
-NR^TwoS (O)_Two-, -NR^TwoS (O)_TwoCR^TwoR^2a-, -CR^TwoR^2aS (O)_TwoNR^Two, -NR^TwoS (O)_TwoNR^Two-, -C (O) NR^Two-, -NR^TwoC (O)-, -C
(O) NR^TwoCR^TwoR^2a-, -NR^TwoC (O) CR^TwoR^2a-, -CR^2aR^2aC (O)
NR^Two-, -CR^TwoR^2aNR^TwoC (O)-, -NR^TwoC (O) O-, -OC (O) N
R^Two-, -NR^TwoC (O) NR^Two-, -NR^Two-, -NR^TwoCR^TwoR^2a-, -CR^TwoR^{Two a} NR^Two-, O, -CR^TwoR^2aO- and -OCR^TwoR^2aY is selected from (CH_Two)_rNR^TwoR^2a(However, XY does not form NN, ON, or SN bonds), 0 to 2 R^4aC substituted with_{Three ~ Ten}Containing a carboxylic acid residue and 1-4 heteroatoms selected from the group consisting of N, O, and S
0 to 2 R^4aR is selected from a 5-10 membered heterocyclic ring substituted with^FourIs, in each case, H, ＯO, (CH_Two)_rOR^Two, F, Cl, Br, I, C _{1 ~ Four} Alkyl, -CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2c , NR^TwoC (O) R^2b, C (O) NR^TwoR^2a, NR^TwoC (O) NR^TwoR^2a, CH (=
NR^Two) NR^TwoR^2a, CH (= NS (O)_TwoR^Five) NR^TwoR^2a, NHC (= NR^Two) N
R^TwoR^2a, C (O) NHC (= NR^Two) NR^TwoR^2a, SO_TwoNR^TwoR^2a, NR^TwoSO_Two NR^TwoR^2a, NR^TwoSO_Two-C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, (C
F_Two)_rCF_Three, NCH_TwoR^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, N (CH_Two)_Two(CH_Two)_tR^{1 '}, O (CH_Two)_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two)_tR ^{1 '} Or one R^FourR is selected from a 5- to 6-membered aromatic heterocyclic group containing 1-4 heteroatoms selected from the group consisting of N, O, and S;^4aIs, in each case, H, ＯO, (CH_Two)_rOR^Two, (CH_Two)_r-F, (CH_Two)_r-Br, (CH_Two)_r-Cl, Cl, Br, F, I, C_{1 ~ Four}Alkyl, -C
N, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2c, NR^TwoC (O) R^{Two b} , C (O) NR^TwoR^2a, C (O) NH (CH_Two)_TwoNR^TwoR^2a, NR^TwoC (O) NR ^Two R^2a, CH (= NR^Two) NR^TwoR^2a, NHC (= NR^Two) NR^TwoR^2a, SO_TwoNR^Two R^2a, NR^TwoSO_TwoNR^TwoR^2a, NR^TwoSO_Two-C_{1 ~ Four}Alkyl, C (O) NHSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^FiveAnd (CF_Two)_rCF_ThreeChoose from
Or one R^4aRepresents 1-4 selected from the group consisting of N, O, and S
0 to 1 R containing two heteroatoms^FiveR is selected from a 5- to 6-membered aromatic heterocyclic group substituted with^4bIs, in each case, H, ＯO, (CH_Two)_rOR^Three, F, Cl, Br, I, C_{1 ~ Four}Alkyl, -CN, NO_Two, (CH_Two)_rNR^ThreeR^3a, (CH_Two)_rC (O) R ^Three , (CH_Two)_rC (O) R^3c, NR^ThreeC (O) R^3a, C (O) NR^ThreeR^3a, NR^ThreeC
(O) NR^ThreeR^3a, CH (= NR^Three) NR^ThreeR^3a, NR^ThreeC (= NR^Three) NR^ThreeR^3a,
SO_TwoNR^ThreeR^3a, NR^ThreeSO_TwoNR^ThreeR^3a, NR^ThreeSO_Two-C_{1 ~ Four}Alkyl, NR^ThreeS
O_TwoCF_Three, NR^ThreeSO_Two-Phenyl, S (O)_pCF_Three, S (O)_p-C_{1 ~ Four}Alkyl, S (O)_p-Phenyl, and (CF_Two)_rCF_ThreeSelected from; R^FiveIs, in each case, CF_Three, C_{1 ~ 6}Alkyl, 0-2 R⁶And 0 to 2 R⁶R selected from benzyl substituted with⁶Is, in each case, H, OH, (CH_Two)_rOR^Two, Halo, C_{1 ~ Four}Alkyl,
CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, NR^TwoC (O) NR^TwoR^2a, CH (= NH) NH_Two, NHC (= NH) NH_Two , SO_TwoNR^TwoR^2a, NR^TwoSO_TwoNR^TwoR^2a, And NR^TwoSO_TwoC_{1 ~ Four}Selected from alkyl; R⁷Is in each case H, OH, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl carbonyl, C_{1 ~ 6}Alkoxy, C_{1 ~ Four}Alkoxycarbonyl, (CH_Two)_n-Phenyl,
C_{6 ~ Ten}Aryloxy, C_{6 ~ Ten}Aryloxycarbonyl, C_{6 ~ Ten}Aryl methylcarbonyl, C_{1 ~ Four}Alkylcarbonyloxy C_{1 ~ Four}Alkoxycarboni
Le, C_{6 ~ Ten}Arylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{1 ~ 6}Alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C_{1 ~ Four}A
Selected from alkoxycarbonyl; R⁸Is, in each case, H, C_{1 ~ 6}Alkyl and (CH_Two)_n-Phenyl; or R⁷And R⁸Combine to form a member selected from the group consisting of N, O, and S
Form a 5 or 6 membered saturated ring containing 0 to 1 additional heteroatoms
R⁹Is, in each case, H, C_{1 ~ 6}Alkyl and (CH_Two)_nN is in each case selected from 0, 1, and 3; m is in each case selected from 0, 1, and 2 p is in each case selected from 0, 1, and 2 R is selected from 0, 1, 2, and 3 in each case; s is selected from 0, 1, and 2 in each case; t Is in each case selected from 0, 1, 2, and 3; provided that D-E-G- (CH_Two)_s-And -ZAB are both benzamido.
Not a gin.

[2] In a preferred embodiment, the present invention provides a novel compound represented by formula Ia-Ih.

[0032]

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Wherein the groups DE- and -ZAB are attached to adjacent atoms on the ring; R is H, Cl, F, Br, I, (CH ₂ ) _t OR ^3, C _{1 ~ 4} is selected from alkyl, _{OCF 3, CF 3, C (} O) NR 7 R 8, and _{^{(CR 8 R 9) t NR}} 7 R 8; Z _{is, CH 2 O, OCH 2,} CH ₂ NH, NHCH ₂ , C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (
CH ₂ ), SO ₂ NH and NHSO ₂ , wherein Z does not form an N—N, N—O, NCH ₂ N, or NCH ₂ O bond with ring M or group A; of 0-2 is substituted with R ⁴ carbocyclic and heterocyclic ring systems; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl , Imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4
-Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,2
5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl B is selected from the group consisting of Y, XY, NR ² R ^2a , C ( = NR ² ) NR ² R ^2a and NR ² C (=
NR ²⁾ is selected from NR ² R ^2a; X is, C _{1 ~ 4} alkylene, -C (O) -, - C (= NR) -, - CR 2 (NR 2 R 2a) -, - C (O ^{) CR 2 R 2a -, -} CR 2 R 2a C (O), - C (O) NR 2 -, -NR 2 C (O) -, - C (O) NR 2 CR 2 R 2a -, - NR ^{2 C (O) CR 2 R} 2 a -, - CR 2 R 2a C (O) NR 2 -, - CR 2 R 2a NR 2 C (O) -, - NR 2 C (
^{O) NR 2 -, - NR} 2 -, - NR 2 CR 2 R 2a -, - CR 2 R 2a NR 2 -, O, -C
R is selected from R ² R ^2a O— and —OCR ² R ^2a —; Y is NR ² R ^2a , provided that XY does not form an NN or ON bond; A carbocyclic and heterocyclic ring system substituted with 0 to 2 R ^4a ; cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, Oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,
2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-
Selected from one of triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzoisothiazolyl, and isoindazolyl; Selected from cyclic heterocyclic ring systems;

[0034]

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K is selected from O, S, NH and N.

[3] In a more preferred embodiment, the present invention provides a novel compound represented by formula IIa-IIf.

[0037]

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In the formula, Z represents C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (
O) NH, C (O) N (CH ₃ ), CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH, and NHSO ₂ , wherein Z is a ring M or It does not form NN or NCH ₂ N bonds with group A.

[4] In an even more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf. Wherein E is phenyl substituted with R or 2-pyridyl substituted with R; D is NH ₂ , NHCH ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ , and C (CH ₃₎ is selected from ₂ NH _2, provided that, D is is substituted at the ortho position relative to the ring M on E; R is selected H, OCH _3, Cl, and the F You.

[5] In an even more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf. In the formula, DE is 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2- (methylamino) phenyl, 4-methoxy- 2-aminomethylphenyl, 4-methoxy-
2- (methylaminomethyl) phenyl, 4-methoxy-2- (1-aminoethyl) phenyl, 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-
Cl-2-aminophenyl, 4-Cl-2- (methylamino) phenyl, 4-C
l-2-aminomethylphenyl, 4-Cl-2- (methylaminomethyl) phenyl, 4-Cl-2- (1-aminoethyl) phenyl, 4-Cl-2- (2-amino-2-propyl) Phenyl, 4-F-2-aminophenyl, 4-F-2- (methylamino) phenyl, 4-F-2-aminomethylphenyl, 4-F-2- (methylaminomethyl) phenyl, 4-F- Selected from 2- (1-aminoethyl) phenyl and 4-F-2- (2-amino-2-propyl) phenyl.

[6] In another even more preferred embodiment, the present invention provides a compound of formula IIa-II
A novel compound represented by f is provided. Wherein Z is C (O) CH ₂ and CONH, wherein Z does not form an NN bond with the group A; A is selected from phenyl, pyridyl, and pyrimidyl; substituted with pieces of R ^4; B is, X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and is selected from imidazolyl, and is substituted with 0-1 R ^4a; R ⁴ is , in each _{case, OH, (CH 2) r} OR 2, halo, C _{1 ~ 4} alkyl, (C
^{_{H 2) r NR 2 R 2a}} , and (CF ₂₎ is selected from the _r CF _{3; R} ^4a is, C _{1 ~ 4 alkyl, CF 3, S (O)} p R 5, SO 2 NR 2 R 2a, and to R ⁵ are in each case, CF _3, C _{1 ~ 6} alkyl, selected from phenyl, and benzyl;; - 1 -CF ₃ is selected from tetrazol-2-yl X is CH ₂ or C (O) Y is selected from pyrrolidino and morpholino.

[7] In another even more preferred embodiment, the present invention provides a compound of formula IIa-II
A novel compound represented by f is provided. Wherein A is a group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C
1-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2
- methylphenyl, selected 2-aminophenyl, and 2-methoxyphenyl; B is a group: 2-CF ₃ - phenyl, 2- (aminosulfonyl) phenyl, 2- (methylamino) phenyl, 2- ( Dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholino, 2- (1′-CF ₃ -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl -1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-methyl-1,2,3
-Selected from triazolyl.

[8] In another even more preferred embodiment, the present invention provides compounds of formulas IIa-II
A novel compound represented by f is provided. Wherein E is phenyl substituted with R or 2-pyridyl substituted with R; D is NH ₂ , NHCH ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ , and C (CH ₃₎ is selected from ₂ NH _2, provided that, D is is substituted at the ortho position relative to the ring M on E; R is selected H, OCH _3, Cl, and the F ; Z is, C (O) is CH ₂ and CONH, provided that, Z is not form a linking group a and N-N; a is phenyl, pyridyl, and is selected from pyrimidyl and 0-2 substituted by R ^4; B is X-Y, phenyl, pyrrolidino, morpholino, selected 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R ^4a; R ⁴ are each in the case _{of, OH, (CH 2) r} OR 2, halo, C _{1 4} alkyl, (C
^{_{H 2) r NR 2 R 2a}} , and (CF ₂₎ is selected from the _r CF _{3; R} ^4a is, C _{1 ~ 4 alkyl, CF 3, S (O)} p R 5, SO 2 NR 2 R 2a, and to R ⁵ are in each case, CF _3, C _{1 ~ 6} alkyl, selected from phenyl, and benzyl;; - 1 -CF ₃ is selected from tetrazol-2-yl X is CH ₂ or C (O) Y is selected from pyrrolidino and morpholino.

[9] In an even more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf. In the formula, DE is 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2- (methylamino) phenyl, 4-methoxy- 2-aminomethylphenyl, 4-methoxy-
2- (methylaminomethyl) phenyl, 4-methoxy-2- (1-aminoethyl) phenyl, 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-
Cl-2-aminophenyl, 4-Cl-2- (methylamino) phenyl, 4-C
l-2-aminomethylphenyl, 4-Cl-2- (methylaminomethyl) phenyl, 4-Cl-2- (1-aminoethyl) phenyl, 4-Cl-2- (2-amino-2-propyl) Phenyl, 4-F-2-aminophenyl, 4-F-2- (methylamino) phenyl, 4-F-2-aminomethylphenyl, 4-F-2- (methylaminomethyl) phenyl, 4-F- A is selected from 2- (1-aminoethyl) phenyl, and 4-F-2- (2-amino-2-propyl) phenyl; A is a group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C
1-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2
- methylphenyl, selected 2-aminophenyl, and 2-methoxyphenyl; B is a group: 2-CF ₃ - phenyl, 2- (aminosulfonyl) phenyl, 2- (methylamino) phenyl, 2- ( Dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholino, 2- (1′-CF ₃ -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl -1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-methyl-1,2,3
-A compound selected from triazolyl.

[10] In an even more preferred embodiment, the present invention provides a novel compound of formula IIa.

[11] In an even more preferred embodiment, the present invention provides novel compounds of formula IIb.

[12] In an even more preferred embodiment, the present invention provides novel compounds of formula IIc.

[13] In an even more preferred embodiment, the present invention provides novel compounds of formula IId.

[14] In an even more preferred embodiment, the present invention provides novel compounds of formula IIe.

[15] In an even more preferred embodiment, the present invention provides novel compounds of formula IIf.

[16] In another even more preferred embodiment, the present invention provides compounds of formula IIa-I
A novel compound represented by If is provided. Wherein D is -CN, C (= NR⁸) NR⁷R⁹, C (O) NR⁷R⁸, NR⁷R⁸, And CH_TwoNR⁷R⁸Wherein D is ortho-substituted with respect to ring M on E; E is phenyl substituted with R or pyridyl substituted with R; R is H, Cl , F, OR^Three, CH_Three, CH_TwoCH_Three, OCF_Three, CF_Three, NR⁷R⁸ , And CH_TwoNR⁷R⁸Z is C (O), CH_TwoC (O), C (O) CH_Two, NHC (O), and C (
O) selected from NH, wherein Z does not form an NN bond with ring M or group A
R^1aAnd R^1bAre independently absent or-(CH_Two)_r-R^{1 '}, NCH_Two R^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, N (CH_Two)_Two(CH_Two)_tR^{1 '}, O (CH _Two )_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two)_tR^{1 '}Is selected from
Or bond to form 0 to 2 R^Four5-8 membered, partially saturated, containing 0-2 heteroatoms selected from the group consisting of N, O, and S substituted with
Or an unsaturated ring; R^{1 '}Is, in each case, H, C_{1 ~ Three}Alkyl, halo, (CF_Two)_rCF_Three, OR ^Two , NR^TwoR^2a, C (O) R^2c, (CF_Two)_rCO_TwoR^2c, S (O)_pR^2b, NR^Two(CH_Two)_rOR^Two, NR^TwoC (O) R^2b, NR^TwoC (O)_TwoR^2b, C (O) NR^TwoR^2a , SO_TwoNR^TwoR^2a, And NR^TwoSO_TwoR^2bA is the following 0 to 2 R^FourCarbocyclic and heterocyclic ring systems substituted with: phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholini
Thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl
Selected from thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl
B is Y, XY, NR^TwoR^2a, C (= NR^Two) NR^TwoR^2a, And NR^TwoC (=
NR^Two) NR^TwoR^2aX is CH_Two, -CR^Two(CR^TwoR^2b) (CH_Two)_t-, -C (O)-, -C (= NR)-, -CH (NR^TwoR^2a)-, -C (O) NR^Two-, -NR^TwoC (O)-, -NR^TwoC (O) NR^Two-, -NR^TwoAnd Y is NR^TwoR^2aWith the proviso that XY does not form an NN or ON bond; alternatively, Y is the next 0-2 R^FourCarbocyclic and heterocyclic ring systems substituted with: phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,
Morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isothio
Xazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl,
Imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3
-Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadia
Zolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2
1,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl
Ryl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-to
Razolyl, and one of 1,3,4-triazolyl; R^FourIs in each case ＝ O, OH, Cl, F, C_{1 ~ Four}Alkyl, (CH_Two)_r NR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, C (O) NR^TwoR^2a , CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^TwoR^2a, NR^TwoSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, And (CF_Two)_rCF_ThreeFrom
Selected; R^4aIs in each case ＝ O, OH, Cl, F, C_{1 ~ Four}Alkyl, (CH_Two)_r NR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, C (O) NR^TwoR^2a , CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^TwoR^2a, NR^TwoSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, (CF_Two)_rCF_Three, And 1
-CF_Three-Tetrazol-2-yl; R^FiveIs, in each case, CF_Three, C_{1 ~ 6}Alkyl, 0-2 R⁶And 0 to 2 R⁶R selected from benzyl substituted with⁶Is, in each case, H, ＯO, OH, OR^Two, Cl, F, CH_Three, CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, CH (= NH) NH_Two, NHC (= NH) NH_Two, And SO_TwoNR^TwoR^2aSelected from
R; R⁷Is in each case H, OH, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl carbonyl, C_{1 ~ 6}Alkoxy, C_{1 ~ Four}Alkoxycarbonyl, benzyl, C_{6 ~ Ten}Aryloxy, C_{6 ~ Ten}Aryloxycarbonyl, C_{6 ~ Ten}Arylmethylcarbo
Nil, C_{1 ~ Four}Alkylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{6 ~ Ten} Arylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{1 ~ 6}Alkylamino
Carbonyl, phenylaminocarbonyl, and phenyl C_{1 ~ Four}Alkoxycal
Selected from Bonyl; R⁸Is, in each case, H, C_{1 ~ 6}Selected from alkyl and benzyl; alternatively, R⁷And R⁸Combine to form a morpholino group; R⁹Is, in each case, H, C_{1 ~ 6}Selected from alkyl and benzyl. [17] In another even more preferred embodiment, the present invention provides a compound of formula IIa-II
A novel compound represented by f is provided. Wherein E is phenyl substituted with R or 2-pyridyl substituted with R; R is H, Cl, F, OCH_Three, CH_Three, OCF_Three, CF_Three, NH_Two, And CH_Two NH_TwoZ is C (O) CH_TwoAnd C (O) NH, wherein Z does not form an NN bond with the group A;^1aIs H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH_Three, NR^TwoR^2a, S
(O)_pR^2b, CH_TwoS (O)_pR^2b, CH_TwoNR^TwoS (O)_pR^2b, C (O) R^TwoC, CH_TwoC (O) R^2c, C (O) NR^TwoR^2a, And SO_TwoNR^TwoR^2aSelected from
R^1bIs H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH_Three, NR^TwoR^2a, S
(O)_pR^2b, CH_TwoS (O)_pR^2b, CH_TwoNR^TwoS (O)_pR^2b, C (O) R^2c,
CH_TwoC (O) R^2c, C (O) NR^TwoR^2a, And SO_TwoNR^TwoR^2aA is the following 0 to 2 R^FourCarbocyclic and heterocyclic ring systems substituted with: phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazo
B is selected from Y and XY; X is CH_Two, -CR^Two(CR^TwoR^2b)-, -C (O)-, -C (= NR)-, -CH (NR^TwoR^2a)-, -C (O) NR^Two-, -NR^TwoC (O)-, -NR^TwoC (
O) NR^Two-, -NR^TwoAnd Y is NR^TwoR^2aWith the proviso that XY does not form an NN or ON bond;^4aCarbocyclic and heterocyclic ring systems substituted with
Nil, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpho
Linyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxa
Zolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imi
Dazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-o
Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl
1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4
-Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl
, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-tria
Zolyl, and one of 1,3,4-triazolyl; R^TwoIs, in each case, H, CF_Three, CH_ThreeR, benzyl, and phenyl;^2aIs, in each case, H, CF_Three, CH_Three, Benzyl, and phenyl
Selected; R^2bIs, in each case, CF_Three, OCH_Three, CH_ThreeR, benzyl, and phenyl; R^2cIs, in each case, CF_Three, OH, OCH_Three, CH_Three, Benzyl, and phenyl;^TwoAnd R^2aIs linked to a 5- or 6-membered, partially saturated, containing 0-1 additional heteroatom selected from the group consisting of N, O, and S.
Unsaturated or unsaturated rings; R^ThreeIs, in each case, H, CH_Three, CH_TwoCH_Three, And phenyl
R^3aIs, in each case, H, CH_Three, CH_TwoCH_ThreeAnd phenyl; R^FourIs in each case OH, Cl, F, CH_Three, CH_TwoCH_Three, NR^TwoR^2a, CH_TwoNR^TwoR^2a, C (O) R^2b, NR^TwoC (O) R^2b, C (O) NR^TwoR^2a,and
CF_ThreeSelected from; R^4aIs in each case OH, Cl, F, CH_Three, CH_TwoCH_Three, NR^TwoR^2a, C
H_TwoNR^TwoR^2a, C (O) R^2b, C (O) NR^TwoR^2a, SO_TwoNR^TwoR^2a, S (O)_p R^Five, CF_Three, And 1-CF_Three-Tetrazol-2-yl; R^FiveIs, in each case, CF_Three, C_{1 ~ 6}Alkyl, 0-2 R⁶A phenyl, and one R⁶R selected from benzyl substituted with R;⁶Is, in each case, H, OH, OCH_Three, Cl, F, CH_Three, CN, NO_Two,
NR^TwoR^2a, CH_TwoNR^TwoR^2a, And SO_TwoNR^TwoR^2aSelected from; R⁷Is in each case H and C_{1 ~ Three}R selected from alkyl;⁸Is, in each case, H, CH_Three, And benzyl; R⁹Is, in each case, H, CH_Three, And benzyl; t is in each case selected from 0 and 1. [18] In another even more preferred embodiment, the invention provides compounds of formula IIa-II
A novel compound represented by f is provided. Where D is NR⁷R⁸, And CH_TwoNR⁷R⁸Wherein D is substituted ortho to ring M on E;^1aIs absent or H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH _Three , NR^TwoR^2a, S (O)_pR^2b, C (O) NR^TwoR^2a, CH_TwoS (O)_pR^2b, CH _Two NR^TwoS (O)_pR^2b, C (O) R^2c, CH_TwoC (O) R^TwoC and SO_TwoNR^Two R^2aSelected from; R^1bIs absent or H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH _Three , NR^TwoR^2a, S (O)_pR^2b, C (O) NR^TwoR^2a, CH_TwoS (O)_pR^2b, CH _Two NR^TwoS (O)_pR^2b, C (O) R^2b, CH_TwoC (O) R^2b, And SO_TwoNR^TwoR ^2a A is the following 0 to 2 R^FourB is selected from Y and XY; X is selected from -C (O)-and O Y is NR^TwoR^2aWith the proviso that XY does not form an ON bond; or Y is 0-2 R^4aCarbocyclic and heterocyclic ring systems substituted with
Nil, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, i
R is selected from midazolyl, and one of 1,2,3-triazolyl; R^TwoIs, in each case, H, CF_Three, CH_ThreeR, benzyl, and phenyl;^2aIs, in each case, H, CF_Three, CH_Three, Benzyl, and phenyl
Selected; R^2bIs, in each case, CF_Three, OCH_Three, CH_ThreeR, benzyl, and phenyl; R^2cIs, in each case, CF_Three, OH, OCH_Three, CH_Three, Benzyl, and phenyl;^TwoAnd R^2aCombine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino; R^FourIs, in each case, Cl, F, CH_Three, NR^TwoR^2aAnd CF_ThreeSelected from
R^4aIs, in each case, Cl, F, CH_Three, SO_TwoNR^TwoR^2a, S (O)_pR^Five, And CF_ThreeSelected from; R^FiveIs, in each case, CF_ThreeAnd CH_ThreeSelected from; R⁷Is, in each case, H, CH_Three, And CH_TwoCH_ThreeSelected from; R⁸Is in each case H and CH_ThreeIs selected from

[19] Particularly preferred compounds of the present invention are selected from the following group: 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- ( 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- ( 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxy) Phenyl)-
1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl) -1H-pyrazole-5- (N- (2'-sulfamide- [1,1 '
] -Bifen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 '] -Bifene-4-
Yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-methylsulfonyl- [1,1 ′]-biphen-4) −
Yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,
1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide -[1,1 ']-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- ( 3-fluoro-2'-methylsulfonyl- [1,1 ']-
Bifen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1 , 1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ′]-Bifen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole 5- (N- (3-fluoro-2′-methylsulfonyl- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro -2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N -(4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (1-pyrroli Dinocarbonyl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl)
Carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl)
Carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl- 1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5 -(N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N -(5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoate) Xyphenyl)
-1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) ) -1H-Pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridine-2)
-Yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methylsulfonyl) phenyl) pyridine-2-
Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl)
Pyridin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxy Phenyl) -1H-pyrazole-5- (N- (5-((2-methylsulfonyl)
Phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidine -2-
Yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidine-2-
Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyrimidin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl ) -1H-Pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidine-
2-ethyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methylsulfonyl) phenyl) pyrimidine-2
-Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl)
Pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxy Phenyl) -1H-pyrazole-5- (N- (5-((2-methylsulfonyl)
Phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1) -Yl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) Phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl)
Phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) ) -1H-Pyrazole-5- (N- (4-((2-methyl) imidazo-
1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazol-5- (N- (4-((5-methyl) imidazo-1-yl ) Phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) Carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl)
Phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl ) -1H-Pyrazole-5- (N- (4-((5-methyl) imidazo-
1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo -1-yl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) Imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl -4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-amino Methyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoro L-methyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; and a pharmaceutically acceptable salt thereof.

[20] Particularly preferred compounds of the present invention are selected from the following group: 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 5-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-3- (N- (2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N, N-dimethylaminomethyl-4-methoxyphenyl) -1H-pyrazole- 5- (N- (2'-N-methylsulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxy Phenyl)
-1H-pyrazole-5- (N- (2'-sulfamide- [1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) )
-1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl)
Carboxamide; N-benzylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxamide)
Piperidine; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5- (2'-sulfonamido) phenyl) pyrid-2-yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5- (pyrid-2-yl)) pyrid-2-yl) carboxamide; N-benzyl-4- (3-trifluoromethyl-1- (2-aminomethyl -4
-Methoxyphenyl) -1H-pyrazole-5-carboxamido) piperidine; N-phenylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5 Carboxamido) piperidine; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ']-Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ']-Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5 -(N- (3-fluoro-2'-sulfamide-
[1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (2-methylsulfonyl- [1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (2-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4 -Fluorophenyl)
-1H-pyrazole-5- (N- (4- (N-((N'-methylsulfonyl) iminoyl) pyrrolidino)) phenyl) carboxamide; 3-trifluoromethyl-1- (2- (N-glycyl) Aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoro Methyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2
'-Methylsulfonyl- [1,1']-biphen-4-yl)) carboxamide; 3- (trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H-
Pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-
4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]-biphene) -4
-Yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-aminosulfonyl- [1,1 ' ]
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [ 1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N- (glycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ' -Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-((N- (N-methylglycyl) aminomethyl) phenyl) -1H-pyrazole -5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-carboxamidophenyl) -1H -Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-cyanophenyl) -1H-pyrazole-
5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 1- (2'-aminomethylphenyl) -5-[[(2 '-Methylsulfonyl)
-3-fluoro- [1,1 ']-biphen-4-yl] aminocarbonyl] -tetrazole; 1- (2'-aminomethylphenyl) -5-[(2'-aminosulfonyl- [
1,1 ′]-biphen-4-yl) aminocarbonyl] -tetrazole; 1- [2- (aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)- (2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorophenyl) -1H-pyrazole-5- ( N- (4- (2-methylsulfonyl- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorofluorophenyl) -1H-pyrazole-5- (N- (4- (2- Sulfamide- [1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorophenyl) -1H-pyrazole-5- (N- (N'-methylsulfonyl) iminoyl )
Pyrrolidino)) phenyl) carboxamide; 3-trifluoromethyl-1- (2- (N-glycyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′- Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole- 5- (N- (3-fluoro-2
'-Aminosulfonyl- [1,1']-biphen-4-yl)) carboxamide; 3- (trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H
-Pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl)- 1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]-biphen-4
-Yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-aminosulfonyl- [1,1 '] −
Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1 , 1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N- (glycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ' -Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-((N- (N-methylglycyl) aminomethyl) phenyl) -1H-pyrazole -5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-carboxamidophenyl) -1H -Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-cyanophenyl) -1H-pyrazole-
5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 1- (2'-aminomethylphenyl) -5-[[(2 '-Methylsulfonyl)
-3-fluoro- [1,1 ']-biphen-4-yl] aminocarbonyl] -tetrazole; 1- (2'-aminomethylphenyl) -5-[(2'-methylsulfonyl)-
[1,1 ′]-biphen-4-yl] aminocarbonyl] -tetrazole; 1- [2- (aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl) -[1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)- (2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)-(2′-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2′-pyrrolidinomethyl)-[1,1 ′]-biphen-4
-Yl) aminocarbonyl] pyrazole; and 1- [2- (aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2′-hydroxymethyl)-[1,1 ′]-biphen-4
-Yl) aminocarbonyl] pyrazole; and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. Offer things.

In a third embodiment, the present invention is a method of treating or preventing a thromboembolic disorder, comprising treating a patient in need thereof with a therapeutically effective amount of a compound of claim 1 or a compound thereof. A method for administering a pharmaceutically acceptable salt is provided.

Definitions The compounds described herein may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of a racemate or synthesis from optically active starting materials, are well known in the art. Olefins, C
Many geometric isomers, such as = N double bonds, can also be present in the compounds described herein, and all these stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomers. Unless a particular stereochemistry or isomer is specifically indicated, all chiral, enantiomeric, racemic, and all geometric isomers are intended in structure. All methods used to prepare the compounds of the present invention and intermediates made herein are considered to be part of the present invention.

The term “substituted,” as used herein, means that one or more hydrogen atoms on the specified atom is replaced with one selected from the indicated group. With the proviso that the normal valency of the specified atom must not be exceeded and that the substituent gives a stable compound. When the substitution is keto (ie, = O),
Two hydrogen atoms on the atom are replaced. The keto substituent is absent or is an aromatic moiety.

The present invention is intended to include all isotopes of atoms occurring in the present invention.
Isotopes include those atoms having the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14.

When a variable (eg R ⁶ ) occurs more than one time in a compound's structure or formula, the definition of each instance is independent of the other. Thus, for example, where a group is indicated as being substituted with 0-2 R ⁶ , the group may be optionally substituted with up to 2 R ⁶ groups, in each case R ⁶ Is independently selected from the definition of R ⁶ . Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, the substituent may be bonded to any atom in the ring. Where a substituent is listed with the remainder of the compound of a given formula with no indication as to which atom of the substituent it is attached to, then the substituent is identified as It may be bonded via an atom. The combination of substituents and / or variables is
It is only acceptable if the combination gives a stable compound.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
Includes s-butyl, t-butyl, n-pentyl, and hexyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.
(For example, in -CvFw, V = 1 to 3 and W = 1 to 2v + 1). Specific examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,
Examples include, but are not limited to, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups such as cyclopropyl, cyclobutyl, cyclopentyl and the like. "Alkenyl" includes any straight or branched hydrocarbon chain, such as ethenyl, propenyl, and the like, and one or more unsaturated carbon atoms which may be at any stable site along the carbon chain. It is intended to include carbon bonds. "Alkynyl" refers to a hydrocarbon chain of any straight or branched configuration, such as ethenyl, propenyl, and the like, and one or more unsaturated carbon atoms at any stable site along the carbon chain. -It is intended to include a carbon triple bond.

“Halo” or “halogen” as used herein refers to fluoro, chloro,
It means bromo and iodine. "Counterion" is used to describe a small, negatively charged ionic species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, “carbocyclic group” or “carbocyclic residue” refers to a stable 3-7 membered monocyclic or bicyclic or 7-13 membered bicyclic or Means tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]
Bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin ), But is not limited to these.

As used herein, the term “heterocyclic group” or “heterocyclic system” refers to a stable 5-7 membered monocyclic or bicyclic or 7-10 membered bicyclic Which are saturated, partially unsaturated, or unsaturated (aromatic) and are independently selected from carbon atoms and 1-4 independently selected from the group consisting of N, O and S Includes any bicyclic group composed of heteroatoms and wherein the heterocycle as defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. A heterocycle may be linked to its side groups at either a heteroatom or a carbon atom, which results in a stable structure. The heterocycle described herein is
If the resulting compound is stable, it may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is 1 or less. As used herein, the term "heteroaromatic ring system" or "heteroaryl" refers to a stable 5 to 7 membered monocyclic or bicyclic or 7 to 10 membered bicyclic heterocyclic aromatic. It means that the ring is composed of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. The total number of S and O atoms in the aromatic heterocycle is preferably 1 or less.

Examples of the heterocyclic group include acridinyl, azosinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl , Benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH
Carbazolyl, carbolinyl, chromanyl, chromanyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2
, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isoquinolinyl Isoxazolyl, mozholinyl
inyl), naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5
-Oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiadinyl, phenoxathiinyl, phenoxazinyl, flatazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl , Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,
Pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl,
Quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,1,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,3
4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,
These include, but are not limited to, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. . Preferred heterocyclic groups include pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxaindolyl, and benzoindolyl. Oxazolinyl and isatinoyl include but are not limited to. For example, a fused ring containing the above-mentioned heterocyclic group and a spiro compound are also included.

The phrase “pharmaceutically acceptable” is used herein to mean, within the scope of sound medical judgment, undue toxicity, irritation, allergic reactions, or other problems, or complications. Used to mean those compounds, substances, compositions and / or dosage forms which are suitable for use in contact with human and animal tissues without causing disease and with a reasonable benefit / risk ratio Can be

As used herein, “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds, wherein the parent compound has been modified by converting it to an acid or base salt thereof. . Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines, alkali and organic salts of acidic residues such as carboxylic acids, and the like. It is not limited. Pharmaceutically acceptable salts include, for example, the usual non-toxic or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such common non-toxic salts include:
Salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, Ascorbic acid, pamic acid
id), maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc. And salts prepared from organic acids of

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts comprise reacting these compounds in the free acid or base form of these compounds with a stoichiometric amount of the appropriate acid or base in water or an organic solvent, or a mixture of both. Can be prepared. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing.
ing Company, Easton, PA, p. 1418, 1985,
, The disclosure of which is incorporated herein by reference.

A “prodrug” is used when a prodrug is administered to a mammalian subject.
It is meant to also include a covalently bonded carrier that releases the active parent drug of formula (I) in vivo. Prodrugs of the compounds of formula (I) are prepared by modifying a functional group present on a compound of the invention such that the modification is cleaved, either by normal operation or in vivo, to the parent compound. You. Prodrugs include compounds of formula (I) in which a hydroxy, amine, or sulfhydryl group is linked to any group that, when administered to a mammalian subject, cleaves to give a free hydroxy, amino, or sulfhydryl group, respectively. Compounds are included. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the alcohol and amine functions in the compounds of formula (I). Preferred prodrugs are amidine prodrugs wherein, D is C (= NH) NHR ⁷ is C (= NR ⁷⁾ NH ₂ or a tautomer thereof, R ⁷ is OH, C _{1 ~ 4} alkoxy, C _{6 ~ 10} aryloxy, C _{1 ~ 4} alkoxycarbonyl, C _{6 ~ 10} aryloxycarbonyl, C _{6 ~ 10} aryl methylcarbonyl, C _{1 ~ 4} alkylcarbonyloxy C _{1 ~ 4} alkoxycarbonyl and C _6, It is selected from _1-10 arylcarbonyloxy C _{1 - 4} alkoxycarbonyl. More preferred prodrugs are those wherein R ⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

By “stable compound” and “stable structure” is meant a compound that is robust enough to withstand isolation from the reaction mixture to useful purity and formulation into an effective therapeutic agent.

As used herein, the term “substituted” means that one or more hydrogen atoms on the atom indicated in the expression “substituted” is selected from the indicated group. As long as it does not exceed the normal valency of the designated atom, and the substitution shall provide a stable compound. When the substitution is keto (ie, = 0), two hydrogen atoms on the atom are replaced. The keto substituent is absent or is an aromatic moiety.

A “therapeutically effective amount” is an amount effective to inhibit an HIV infection in a host.
Or it is intended to include an amount of a compound of the present invention or a combined amount of a compound as claimed in the invention, which is effective in treating the syndrome of HIV infection. The combination of the present compound is preferably a synergistic combination. For example, Chou and Talalay, Adv.Enzyme Reg
ul. 22: 27-55 (1984) and the like, there is a synergy when the effect of the present compound (in this case, inhibition of HIV replication) is administered in combination, when administered as a single agent Is greater than the additive effect of this compound. In general, the synergistic effect is
It is most clearly demonstrated at non-maximal concentrations of the compound. Synergy is in terms of lower toxicity, greater antiviral effect, or some other beneficial combination effect compared to the individual components.

Synthetic Methods The compounds of the present invention can be prepared by a number of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized by the methods described below, as well as synthetic methods or modifications thereof known to those skilled in the art relating to synthetic organic chemistry. Preferred methods include, but are not limited to, those described below. The reaction is performed in a solvent appropriate to the reagents and materials employed and suitable to effect the transformation. As will be appreciated by those skilled in the art of organic synthesis, the functional groups present on the molecule must be consistent with the desired transformation. Thus, in order to obtain the desired compounds of the present invention, it will often be necessary to judge the order of the synthetic steps and to select one particular method scheme prior to the other. It is understood that another major consideration in designing synthetic routes in the art is the correct choice of protecting groups used to protect the reactive functional groups present on the compounds according to the present invention. Greene and Wuts provide an authoritative account of the many options available to those skilled in the art (see “Protective Groups in Organic Synthesis S”).
ynthesis), Wiley and Sons, 1991). All references cited herein are hereby incorporated by reference.

Compounds of formula I wherein Ring M is pyrrole can be prepared by the methods described in Schemes 1-9. Scheme 1 shows a method for preparing pyrroles wherein the group QE is attached to the pyrrole nitrogen, where Q is a functional group that can be converted to D of formula I and ^Re is R ^f is a functional group that can be converted to ^ZAB of formula I and R ^f is a functional group that can be converted to R ^1a of formula I. Oxidation of the furan with bromine in acetic acid, 2,5-diacetoxy-dihydrofuran is obtained which is reacted with an amine Q-E-NH ₂ can be obtained pyrrole. By performing Vilsmeier-Haak formylation using phosphorus oxychloride and DMF, the pyrrole ring can be preferentially acylated at the C-2 position. By oxidizing the obtained aldehyde, a carboxylic acid can be obtained. The carboxylic acid is then converted to the Hoffman degradation of a derivative primary amide (Huisgen et al., Chem. Be.
r. 1960, 93, 65) or Curtius rearrangement of a derived acyl azide ((J.
pack. Chem. 1909.42, 477) can be used to convert to amine derivatives. Derivatives containing a sulfur atom attached to the pyrrole ring,
The pyridine sulfur trioxide complex is directly sulfonated to a sulfonic acid or treated with copper (II) thiocyanate (J. Het. Chem. 1988, 25,
431) It is obtained by subsequently reducing the thiocyanate intermediate with sodium borohydride to give a mercaptan.

[0075]

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Scheme 2 shows a method for preparing pyrroles having QE attached at the 2-position. In this case, R ^f and R ^g are commonly halogen or a bond that can be converted to R ^1a and R ^g of formula I. The Hantzsch pyrrole synthesis is a versatile reaction involving the cyclization of the appropriate β-ketoester with an α-haloketone or aldehyde in the presence of a primary amine (Ber. Dtsch. Chem. Ges. 1).
890, 23, 1474). The β-ketoester can be converted to the acid chloride (X =) by decarbonylation following the addition of the magnesium anion of the potassium alkylmalonate.
Cl) (Synthesis 1993, 290).
Alternatively, beta-keto esters can be prepared from the appropriate aldehyde (R = H) by performing oxidation following the R ^e formars ky reaction between α- bromoacetate. Cyclization with an α-haloketone or aldehyde in the presence of a primary amine gives pyrroles. Carboxylic acids are obtained by acid hydrolysis of 3-carboalkoxypyrroles. Pyrroles containing a 3-amino substituent are treated with phosphoryl azide and triethylamine to undergo Curtius rearrangement to give an isocyanate (J. Het. Chem. 1981, 24.33), which is hydrolyzed to 3-aminopyrrole. Can be prepared from acids by obtaining C-
Pyrroles containing a sulfur atom at the 3-position can be prepared from acids by performing the Hunsdiecker method to obtain the 3-bromo derivative. Halogen by an alkyl lithium reagent at low temperature - 3-lithio derivative obtained by performing the metal exchange reaction, which various electrophiles, for example, either obtained directly Ji ols by quenching in S _8, or Cu ( Quenching with (SCN) ₂ gives the thiocyanate, which is reduced with sodium borohydride. By further oxidizing the thiols with an oxidizing agent such as KMnO ₄ , a sulfonic acid derivative can be obtained.

[0077]

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Scheme 3 shows a method for preparing pyrroles with QE attached at the 3-position. This scheme relies on a very versatile Knorr pyrrole synthesis involving the condensation of α-aminoketones with β-ketoesters. α-Aminoketones can be prepared from β-ketoesters (Scheme 2) by nitration followed by reduction of zinc / acetic acid. Condensation of α-aminoketones with appropriate β-ketoesters can produce pyrroles in good yields. These intermediates are very versatile and can be converted to pyrroles having various substituents with different substitution patterns. When ^Re (ZAB precursor) is at the 2-position, C-3 esters can be selectively hydrolyzed by oxidative water splitting. It should then be decarboxylated by heating. Hydrolysis of the 2-carboxylic acid can be performed under basic conditions. Amino derivatives can be obtained by Curtius rearrangement of the aforementioned acids. C
In order to prepare a compound having a sulfur atom bonded to the -2 atom, C-2 unsubstituted pyrroles can be obtained by performing base hydrolysis and decarboxylation. These pyrroles can be converted to thiols (Cu (
SCN) ₂ , then NaBH ₄ ) and sulfonic acids (pyridine SO ₃ complex or chlorosulfonic acid). R ^1a included in Formula I can be obtained from either the residual ester or R ^f . Alternatively, thiol and sulfonic acid derivatives can be obtained from C-2 acids by manipulation of carboxylic acid groups, as described above.

[0079]

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Scheme 4 shows a method for preparing pyrrole with QE attached at the 3-position. As described above, pyrroles can be obtained by condensation of α-aminoketones and β-ketoesters. When the C-2 ester is selectively hydrolyzed by hydrolysis under basic conditions and heated to be decarboxylated, 2-unsubstituted pyrroles can be obtained. Then, the C-3 ester is hydrolyzed under acidic conditions to obtain 3-carboxypyrroles. Curtius rearrangement under the conditions described above can produce 3-aminopyrroles. Using this carboxylic acid, 3-mercapto and 3-sulfonic acid derivatives can be prepared. The 3-bromopyrroles can be prepared using the Hunsdiecker method. By performing a halogen-metal exchange reaction using t-BuL at a low temperature, followed by quenching with copper isocyanate, an isocyanate group can be introduced at the C-3 position. Reduction of this intermediate with sodium borohydride gives 3-mercaptopyrrole. Alternatively, the carboxylic acid can be decarboxylated to give pyrroles, which can be protected with a bulky protecting group such as triisopropylsilyl (TIPS). This bulky group leads the electrophilic substitution to C-3 of the pyrrole ring. Thus, the reaction with copper isocyanate is followed by sodium borohydride reduction followed by fluorine-induced TIPS deprotection to give 3-
Mercaptopyrrole can be obtained. N by pyridine sulfur trioxide complex
The sulfonation of the protected pyrrole leads again to the C-3 position of the pyrrole, TIPS
After deprotection, 3-sulfonic acid is obtained.

[0081]

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Another general method of pyrrole synthesis that can be used to prepare compounds of the present invention is shown in Scheme 5. This approach (Cuchaman et al., J. Org. Chem. 1996, 61, 4999) is based on the initial preparation of N-methoxy-N-methylamides followed by the addition of an alkyl Grignard reagent (to produce a ketone), or N-protected α-aminoketones and N-protected α-aminoaldehydes, which can be easily obtained from α-amino acids by reduction with a hydrogenation reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride, Used. These aldehydes and ketones can be reacted with an enolate of another ketone to form an aldol addition product intermediate, which can be cyclized under acidic conditions to form pyrroles. The reaction partners in this approach are very broad and one skilled in the art can choose to prepare the modified pyrroles.

[0083]

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Another general method of synthesizing pyrroles useful for preparing compounds of the present invention is
It is a Paal-Knorr reaction shown in Scheme 6. This reaction involves reacting 1,4-diketoaldehydes or 1,4-ketoaldehydes with primary amines to obtain pyrroles. Starting 1,4-diketoaldehydes and 1,4
-Ketaldehydes can be prepared using standard enolate chemistry or by other methods well known to those skilled in organic synthesis. The reaction is extensive and the starting materials can be chosen to give various pyrroles.

[0085]

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[0086] Scheme 7 illustrates a method capable of converting the compound of Scheme 1 to 6 R ^e is a carboxylic acid ester group to a compound containing a Z-A-B residue. In the amide linker (formula I, Z = -CONH-), when R ^e = carboalkoxy, as described above, this is hydrolyzed to an acid under basic or acidic conditions depending on the type of substitution. be able to. Forming an acid chloride using thionyl chloride;
Subsequently, an appropriate amine H ₂ NAB is added to obtain an amide bond compound. Alternatively, the acid can be coupled to the amine H ₂ NAB in the presence of a suitable peptide coupling agent such as BOP-Cl, HBTU, or DCC. In another method, esters can be directly coupled with an aluminum reagent prepared by adding trimethyl aluminum to the amine H ₂ N- A-B.

The acid can be reduced to an alcohol to form an ether- or thioether-linked compound of formula I (Z = —CH ₂ O—, —CH ₂ S—). The preferred method for this transformation is reduction with borane THF complex or with reduction of the mixed anhydride with sodium borohydride (IBCF = isobutylchloroformate, and NMM = N-methylmorpholine). . Completion of the ether and thioester linked compounds of Formula I is accomplished by the appropriate phenol, thiophenol, or hydroxy- or mercapto heterocyclic group HX-AB (X = O, S) (
(Formula I, A = aryl or heteroaryl) can be easily achieved by the Mitsunobu protocol. Other ethers or esters (
X = S, O) can be prepared after first converting an alcohol to a suitable leaving group such as tosylate. When a X = S, thioesters further oxidized to sulfones (Formula _{I, Z = -CH 2 SO 2} -) can be.

To prepare the amine-linked compound of formula I (Z = —CH ₂ NH—), the alcohol is oxidized to the aldehyde in a number of ways, but two preferred methods are Swe.
rn oxidation and oxidation with pyridinium chlorochromate (PCC). Alternatively, the aldehyde can be converted to V in certain cases as shown in the previous scheme.
It can be prepared directly by direct formylation of the pyrrole ring by the ilsmeier-Haack method. Then, by reductive amination of the appropriate amine H ₂ N-A-B and hydrogenated Anohou sodium hydrogen with an aldehyde, can be obtained amine binding compound.

An aldehyde can also be used to prepare a ketone binding compound of formula I (Z = —COCH ₂ —). By treating with an organometallic nuclide, an alcohol can be obtained. Preferably, the organometallic nuclide (where M = magnesium or zinc) can be prepared from the corresponding halide by treatment with metallic magnesium or zinc. These reagents should readily react with aldehydes to produce alcohols. Oxidation of the alcohol by any of a number of methods, such as Swern oxidation or PCC oxidation, affords ketone binding compounds.

[0090]

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Another compound of Formula I wherein the linking group m / z contains a nitrogen atom bonded to Ring M can be prepared by the methods described in Scheme 8. Amines, by the present child treated with a suitable sulfonyl chloride B-A-SO ₂ Cl in of a base such as triethylamine, sulfonamides (Formula _{I, m / z-NHSO 2} -) can be converted to it can. The amines can be treated with the appropriate acid chloride Cl-CO-AB in the presence of a base, or in the presence of a suitable peptide coupling reagent such as DCC, HBTU or BOP, with the appropriate carboxylic acid HO. By treating with -CO-AB, it can be converted to amides (formula I, Z = -NHCO-). Amines, by performing reductive amination with an appropriate aldehyde OHC-A-B, an amine binding compounds (Formula _{I, Z = -NH 2 CH 2} -) can be converted into.

[0092]

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Another compound of Formula I wherein the linking group Z contains a sulfur atom attached to ring M can be prepared by the method described in Scheme 9. Five processes sulfonic acid in phosphorus chloride, followed by treatment with the appropriate amine H ₂ N-A-B, it is possible to obtain a sulfonamide bond compound (NH- Formula I, Z = -SO _2). Alkylation of thiols with a suitable alkylating agent in the presence of a base gives the thioethers (Formula I, Z =-
SCH _2- ) is obtained. Sulfo down binding compounds by oxidizing these compounds further with various reagents (Formula _{I, Z = -SO 2 CH 2} -) can be obtained.

[0094]

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Compounds of Formula I wherein Ring M is an imidazole can be prepared using the methods described in Schemes 10-16. The N-substituted imidazole derivative can be produced by the general method shown in Scheme 10. In this case, V ′ is V
Or (CH ₂ ) _n V, wherein V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide, and n is 0 and 1. , PG is either hydrogen or a protecting group. Substitution couples imidazole with the halogen-containing fragment QE-Hal in the presence of a catalyst such as Cu / CuBr / base, or Pd / base, followed by conversion of V ′ to (CH ₂ ) _n V. By doing so, it can be performed. Q can then be converted to D, and finally, V can be converted to -ZAB according to the methods outlined in Schemes 7-9. Alternatively, V is ZAB
, Followed by deprotection of N. This product can then be coupled before obtaining the desired imidazole.

[0096]

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One method for preparing amidino-phenyl-imidazole derivatives is Scheme 1
It is shown in FIG. 4-imidazole carboxylic acid is treated with thionyl chloride, then H ₂ and N-A-B coupled in the presence of a base, can then be heated in the presence of a base with 3-fluorobenzonitrile. The amidino group can be formed using a Pinner reaction using standard methods known to those skilled in the art.

[0098]

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The 1,2-disubstituted and 1,5-disubstituted imidazole derivatives can be prepared by the general method described in Scheme 12, wherein R ^1b is either a halogen or an alkyl group And U is an aldehyde, ester, acid, amino, thiolhydroxy, sulfonic acid, sulfonic ester, or methylene halide. Step a involves coupling in the presence of a catalyst such as a base, Cu / CuBr / base, or Pd / base. When R ^1b is hydrogen, it can be deprotonated with a lithium base, formate, formamide, carbon dioxide,
Trapping with sulfonyl chloride (sulfur dioxide followed by chlorin) or isocyanate can give 1,2-disubstituted imidazoles (path b1)
. Further, in pathway ^1b where R ^1b is CH ₃ , U can be oxidized to form U with Seo ₂ , MnO ₂ , NaIO 4 / catalyst RhCl ₃ , or NBS. If R ^1b is hydrogen, a series of deprotections and quenching with a lithium base or trimethylsilyl chloride, followed by a second deprotection with a lithium base, and formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorin) Or quenching with an isocyanate to give 1,5-disubstituted imidazoles (path b2). If R ^1b is not hydrogen, use the method of Route 2 again to
, 5-Disubstituted imidazoles can be obtained (path b3).

[0100]

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A preferred method for making 1,2-disubstituted and 1,5-disubstituted imidazole derivatives is shown in Scheme 13. Imidazole can be heated with 3-fluorobenzonitrile in the presence of a base. Then treated coupling product with an alkyl lithium base, by quenching with ClCO ₂ Me, 1, 2-disubstituted compound. Preparation of H ₂ N-AB in Trimethylaluminum Further treatment with a solution gives the amide, which can be further modified by the Pineer reaction to form the desired compound. The 1,5-disubstituted compounds can be prepared using the same method, except that the first anion is protected and another is formed and then quenched as described above. it can. Further modifications are made after the same method as for the 1,2-disubstituted compounds.

[0102]

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Another method for preparing 1,2-disubstituted imidazole derivatives is shown in Scheme 14. The amide is obtained by reacting an N-substituted imidazole with a cyanate. This amide can then be coupled to group B as described below.

[0104]

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Another method for preparing 1,5-disubstituted imidazole derivatives is shown in Scheme 15. Alkylation with 2-bromoethyl acetate followed by reaction with Gold's reagent in the presence of a base such as NaOMe or LDA yields ester-substituted imidazoles, which can be further modified as described above.

[0106]

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General Production of 2,4,5-Trisubstituted or 4,5-Disubstituted Imidazole Derivatives
The scheme is shown in Scheme 16. Metal halogen of QEG fragment
After the exchange reaction, it is reacted with the indicated amide, brominated with NBS and excess NH _Three And R^1aCO_TwoCyclization with H can give imidazole. Then,
This can be modified as follows:

[0108]

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A general method for preparing 4,5-disubstituted triazole derivatives is shown in Scheme 17. Ethyl propionate can be done in the presence of CuI / Pd,
It can then be reacted with NaN ₃ to form a triazole. This triazole can be converted as described above.

[0110]

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The tetrazole compounds of the invention wherein Z is —CONH— can be prepared as illustrated in Scheme 18. A suitably substituted amine can be acylated with ethyl oxalyl chloride. Dunicia (J. Org. Che)
m. 1991, 395-2400) or Thomas (Synthesis).
1993, 767-768), the resulting amide can be converted to a tetrazole. Converts the amide is first chloride iminoyl, is reacted with NaN _3, it is possible to form the 5-carboethoxy-tetrazole (J.Org.Chem.1993,58,32-35 and Bioor
g. & Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carbethoxytetrazole can then be further modified as described in Scheme 7.

The tetrazole compounds of the present invention wherein Z is —CO— can also be prepared via iminoyl chloride using appropriately substituted acyl chlorides as starting materials (
Chem. Ber. 1961, 1116 and J.M. Org. Chem. 1976
, 41, 1073). The keto-linker can be reduced to a compound where Z is alkyl.

[0113]

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Using the method described in Scheme 18, compounds wherein EQ is attached to the carbon atom of the tetrazole as shown in Scheme 19 can be synthesized. The desired product is then obtained by alkylating or acylating the 5-substituted tetrazole.

[0115]

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The tetrazole compound of the present invention wherein Z is —SO ₂ NH—, —S—, —S (O) —, —SO ₂ — may be prepared from a thiol prepared as shown in Scheme 20. Can be. Reduction of an appropriately substituted thioisocyanate with sodium azide can give 5-thiotetrazole (J. Org. Ch.
em. 1967, 32, 3580-3592). This thio compound was prepared according to Scheme 9
Can be modified as described in.

The tetrazole compounds of the present invention wherein Z is —O— can be prepared by a method similar to that described in Scheme 20, using an appropriately substituted isocyanate as a starting material. The hydroxy compound can be modified analogously to the thiols described in Scheme 9.

[0118]

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The tetrazole compounds of the present invention wherein Z is —NH—, —NHCO—, —NHSO ₂ — can be prepared from 5-aminotetrazole, where 5-aminotetrazole is as shown in Scheme 21. Can be prepared by the Smile rearrangement. Thio compounds prepared as described in Scheme 20 can be alkylated using 2-chloroacetamide. The resulting compound is then refluxed in ethanolic sodium hydroxide to give the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 33).
31-3334). The resulting 5-amino-tetrazole is then alkylated or acylated to form the desired product.

[0120]

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The pyrazoles of formula I (such as those described in Scheme 22) can be prepared by condensation of an appropriately substituted hydrazine with various diketoesters. This type of condensation is generally effected by the regioisomers of the pyrazole.
), Which can be separated efficiently by silica gel column chromatography. This ester can be converted to ZAB as described above.

Alternatively, in Scheme 22, the starting diketone contains CH ₃ instead of CO ₂ Et, then the resulting methylpyrazole is separated and oxidized to afford the pyrazole carboxylic acid as in Scheme 12, pathway b1. Can be formed.

[0123]

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When ketoimidates are used for condensation with hydrazines, the corresponding pyrazole amino esters are obtained (Scheme 23). The conversion of these intermediates to the final compounds of the formula I can be effected by protecting the amino function with a suitable protecting group or by derivatizing (for example, a sulfonamide) and then as described above. Can be carried out by modifying the ester.

[0125]

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As shown in Scheme 24, pyrazoles substituted at the 4-position can be prepared by first brominating the pyrazole (bromine or NBS in dichloromethane or acetic acid). The conversion of 4-bromo-pyrazole to 4-carboxylic acid-pyrazole can be accomplished by a number of methods commonly known to those skilled in the organic arts. Further manipulations as described above provide the pyrazoles of the present invention.

[0127]

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The pyrazoles can also be prepared according to the method described in Scheme 25. Bromo-pyrazoles are formed as in Scheme 24. The QE is then coupled using a Suzuki cross-coupling method with a palladium catalyst. Further modifications are made as described above.

[0129]

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[0130] 5-Substituted phenylpyrazoles can be prepared by the method shown in Scheme 26. The 5-hydroxypyrazole is then triflated (trifl).
ate) (triflic anhydride, lutidine in dichloromethane) or bromide (
Following the conversion to POBr _3), Suzuki cross Palladium the appropriately substituted phenyl boronic acid (p henylboronic acid) - by coupling 5-substituted pyrazoles are produced. This intermediate can then be converted to a 4-bromo derivative as described in Scheme 24 followed by carbonylation to give the appropriate ester, which can be further converted to a compound of Formula I.

[0131]

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The 1-substituted-1,2,3-triazoles of the present invention can be prepared by treating an appropriately substituted azide with various dipolarophiles, as shown in Scheme 27.
Can be prepared (Tetrahedron 1971, 27, 845 and J. Amer. Chem. Soc. 1951, 73. 1207). Generally, a mixture of regioisomers is obtained, which can be separated and manipulated to the triazole carboxylic acid. Subsequent further transformation as described above gives the compounds of the invention.

[0133]

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The 1,2,4-triazoles of the present invention can be prepared by the method of Huisgen et al. (Lieb)
igs Ann. Chem. 1962, 653, 105), which can be obtained by cycloaddition of a nitriliminium nuclide (obtained from treatment of triethylamine and chlorohydrazone) and a suitable nitrile dipolarophile (Scheme 28). This method gives a variety of 1,2,4-triazoles with different substitution patterns at the 1, 3 and 5 positions.

[0135]

Embedded image 1,2,4-Triazoles are described in Zecchi et al. (Synthesis 19
86, 9, 772) by aza-Wittig condensation (Scheme 29).

[0136]

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The 1,2,4-triazoles in which the -ED (Q) substituent is at the 5-position of the triazole can be obtained as shown in Scheme 30.

[0138]

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The 1,3,4-triazoles of the present invention are described in Moderhack et al. (J. Pra.
kt. Chem. 1996, 338, 169).
As shown in Scheme 31, this reaction involves the condensation of a carbazide with an appropriately substituted commercially available thioisocyanate to form a cyclic thiourea. Alkylation or nucleophilic substitution on the thiono-urea intermediate produces a thio-alkyl or aryl intermediate, which is hydrolyzed, oxidized, and decarboxylated to form a 5-H2 thio-triazole intermediate; This can be converted to the compounds of the present invention. Alternatively, the thio-urea intermediate can be oxidized directly to the 2-H triazole, which can then be converted to an ester and modified as described above. This thio-urea intermediate can also be oxidized to the sulfonyl chloride by the methods described above.

[0140]

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The imidazole nucleus shown in Scheme 32 can be prepared by condensing 3-cyanoaniline with n-butylglyoxylate to produce the imine, which is then treated with tosyl MIC in basic methanol to afford the desired imidazole nucleus. By producing an imidazole compound of formula (I). The coupling of the ester under standard conditions then gives the various analogs, which can then be further manipulated to produce, for example, benzylamine or benzamidines.

[0142]

Embedded image

Compounds of the present invention wherein AB is biphenylamine or a similar amine can be prepared as shown in Scheme 33. 4-bromoaniline is Bo
protected as c-derivatives, under Suzuki's conditions (Bioorg. Med. Che.
m. Lett. 1994, 189). An aminobiphenyl compound can be obtained by deprotection with TFA. Other similar amines wherein A and / or B are heterocyclic groups are
Can be prepared by the same method using appropriately substituted boronic acids and aryl bromides. The desired product can also be obtained by first coupling the bromoaniline to the core ring structure as described above and then performing the Suzuki reaction.

[0144]

Embedded image

Compounds of the present invention wherein AB is AXY can be prepared as the piperazine derivatives shown in Scheme 34.

[0146]

Embedded image

Scheme 35 illustrates a method of coupling a cyclic group where X = NH, O, or S.

[0148]

Embedded image

When B is defined as XY, the following applies. Groups A and B are
It is either obtained from commercial sources known in the literature or is easily synthesized by using standard procedures known to those skilled in organic synthesis. The necessary reactive functional groups added to the analogs of A and B can also be obtained from commercial sources known in the literature, or by using standard procedures known to those skilled in organic synthesis. Is synthesized. The following table outlines the chemistry required to link A to B.

[0150]

[Table A]

[0151]

[Table A-1]

The chemistry of Table A is based on the presence or absence of a trialkylamine base in an aprotic solvent such as chlorocarboxylic, pyridine, benzene or toluene at a temperature ranging from −20 ° C. to the reflux point of the solvent. Can be performed in the presence.

[0153]

[Table B]

The coupling chemistry in Table B can be performed by various methods. The Grignard reagent required for Y is prepared from the halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at a temperature from 0 ° C. to the reflux point of the solvent. The Grignard reagent is used under very controlled conditions (ie,-
Reacts with a large excess of the acid chloride, or with a catalytic or stoichiometric copper dimethyl bromide sulfide complex in dimethyl sulfide as a solvent, or a variant thereof be able to. Other methods available include Grign
The ard reagent is replaced with a cadmium reagent, and the procedure of Carson and Prout (O
rg. Syn. Col. 3, 601: 1955) or by Fiandanase et al. (Tetrahedron Lett., 480).
Page 5, coupling mediated by binding or manganese (II) catalyst is mediated by Fe (acac) ₃ according to 1984) (Cahiez and Laboue,
Tetrahedron Lett. 33 (No. 31), p. 4437, 199
2 years).

[0155]

[Table C]

The ether and thioether bonds in Table C were prepared in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at ambient temperature. At a temperature ranging from to the reflux point of the solvent used.

[0157]

[Table D]

The thioethers of Table C serve as convenient starting materials for preparing the sulfoxide and sulfone analogs of Table D. Combining wet alumina and oxone can provide a reliable reagent for oxidizing thioethers to sulfoxides. On the other hand, sulfone is obtained by oxidation with m-chlorofiltered benzoic acid.

[0159]

[Table E]

Table E shows some methods for converting the functional group Q to the group D of the formula I. Although not all of the possible functional groups for Q and D are listed, and the synthetic methods proposed are not extensive, Table E shows that a person skilled in the art of organic synthesis would be able to synthesize compounds of Formula I using It is intended to illustrate possible strategies and transformations. Reaction 1 of Table E shows the conversion of nitriles to amidines by the pinner method. Reaction 2 shows the direct reduction of nitrile to methyleneamine by a hydride reducing agent. Reaction 3 demonstrates the usefulness of carboxylic acids, which can be readily derived from their esters or nitriles, if necessary, in the synthesis of methyleneamine. This synthetic route is very flexible because some stable intermediates are generated during the synthesis to the final product. As shown in the table, the formation of an active analog, such as a mixed anhydride, allows the mild reduction of the acid to methylene alcohol, which can then be converted to a leaving group by sulfonylation or halogenation. Or can be protected with a suitable protecting group for conversion later in the synthetic step as required by chemical considerations. Once the methylene alcohol has been so activated, it can be displaced by an effective nitrogen nucleophile, such as the azide anion, again providing another suitable stable analog-methylene azide. It can be used as a protected form of methyleneamine or directly converted to a methyleneamine group by reduction. Reaction 4 addresses the problem of adding an amine function directly by attachment to group E of formula I. Again, the carboxylic acid provides a convenient entry to this choice for group D. Here, the well-known Curtius dislocation is shown. That is, an activated azide can be used to generate an acyl azide, which can be thermally decomposed and rearranged to the corresponding isocyanate. The isocyanate intermediate can then be captured as a stable carbamate by adding the appropriate alcohol and further heating. The carbamate can be used as a stable protecting group for the amine or can be cleaved directly to the desired D. Alternatively, a method in which the isocyanate intermediate is stopped with water to directly obtain an amine is considered to be simple.

Other features of the present invention will become apparent in the following description of exemplary embodiments. Such embodiments are provided for illustration of the invention,
It is not intended to be so limited.

EXAMPLES Example 1 3-Methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-sulfamide- [1,1 ′) ] -Bifen-4-yl)) carboxamide, trifluoroacetate Part A: 2-carboxy-4-methoxyphenylhydrazine: methanol (
2-nitro-5-methoxybenzoic acid (5.0 g) in 150 mL) was treated with hydrogen (5
Shake under 0 psi) atmosphere in the presence of 10% palladium on carbon catalyst (0.5 g) until hydrogen uptake ceased (about 3 hours). The methanol solution was purged with nitrogen, filtered through a pad of Celite® and evaporated. 4.2 g (25.1 mmol) of aniline were obtained; ESI mass spectral analysis m / z (relative intensity) 168 (M + H, 100).

The aniline prepared above (4.2 g, 25.1 mmol) in concentrated hydrochloric acid (50 mL)
1) was cooled to 0 ° C. and sodium nitrite (2.08 g) in cold water (20 mL)
, 30.2 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 30 minutes to 1 hour, then tin (II) chloride dihydrate (17.0 g) in cold concentrated hydrochloric acid (25 mL)
, 75.4 mmol) were added dropwise. The mixture was warmed to ambient temperature for 3-5 hours, then filtered several more times and air dried. The filter cake was broken and further dried in a vacuum oven at 60 ° C. overnight. 8.76 g of 2-carboxy-4-methoxyphenylhydrazine tin salt was obtained.

Part B: Ethyl 2-N- (methoxy) imino-4-oxopentotoanoate: ethylpentotoanoate-2,4-dione (2 in ethanol (100 mL)
4.5 g, 154.9 mmol) and methoxyamine hydrogen chloride (13.58 g)
, 162.6 mmol) of activated 0.3 nm molecular sieves (75
g) at ambient temperature for 18 hours. After removal of the molecular sieves by filtration, dichloromethane (100 mL) was added and the reaction was filtered. The resulting solution was evaporated and the residue was applied to a silica gel column. The title compound was treated with 5: 1 hexane:
Isolation in homogeneous form by elution with ethyl acetate gave 9.09 g of product.

Part C: Ethyl 3-methyl-1- (2-carboxy-4-methoxyphenyl) -1H-pyrazole-5-carboxylate and ethyl 5-methyl-1- (
2-carboxy-4-methoxyphenyl) -1H-pyrazole-3-carboxylate: ethyl 2-N- in acetonitrile (40 mL) and acetic acid (5 mL)
(Methoxy) imino-4-oxopentanoate (1.0 g, 5.35 mmol
l) and crude 2-carboxy-4-methoxyphenylhydrazine (5.83)
g) was stirred at ambient temperature for 3 hours and then heated at reflux for a further 3 hours. The reaction was cooled to ambient temperature, diluted with methylene chloride (150 mL) and filtered. The filtrate was evaporated and the product was isolated by flash chromatography eluting with 10% methanol in chloroform. This material (1.28 g) was co-eluted as a mixture of stereoisomers, as revealed by proton NMR.
ESI mass spectral analysis m / z (relative intensity) 306 (M + H, 100).

Part D: Ethyl 3-methyl-1- (2-hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylate and ethyl 5-methyl-
1- (2-hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-3
-Carboxylate: mixture of regioisomers prepared in Part C (1.28 g, 4
. 2 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to 0 ° C. To this cold solution was added N-methylmorpholine (0.42 g, 4.2 mmol) and isobutyl chloroformate (0.57 g, 4.2 mmol). The reaction was stirred at 0 ° C. for 30 minutes, the precipitate was removed by filtration and the cold solution was added to water (20 mL).
mL) and sodium borohydride (0 mL) in tetrahydrofuran (20 mL).
. (48 g, 12.6 mmol) in a cold (5 ° C.) solution. The reaction was warmed to room temperature over 18 hours. The reaction mixture was evaporated and ethyl acetate (10
(0 mL) and 1N hydrochloric acid (50 mL), then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried and evaporated; three products were isolated by elution of the crude mixture from a silica gel column with 2: 1 hexane: ethyl acetate. The first product eluted is the ring-closed lactone (0.14 g); ESI mass spectral analysis m / z (relative intensity) 245 (M + H, 100). The second product isolated was ethyl 3-methyl-1- (2-hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-5.
Carboxylate (0.18 g), determined by proton NMR experiments; ESI mass spectrometry m / z (relative intensity) 291 (M + H, 100)
. The third product eluted was the regioisomer ethyl 5-methyl-1- (2-
Hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-3-carboxylate (0.14 g); ESI mass spectral analysis m / z (relative intensity) 291 (M + H, 100).

Part E: Ethyl 3-methyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylate: Ethyl 3-methyl-1- (2
-Hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylate (0.18 g, 0.62 mmol) was dissolved in chloroform (20 mL), then methanesulfonyl chloride (0.3 g, 2.6 mmol) and Triethylamine (0.26 g, 2.6 mmol) was added. The reaction is completed in 6 hours,
This was evaporated, dissolved in ethyl acetate (100 mL), washed with 1N hydrochloric acid (50 mL) and brine (50 mL), dried and evaporated to give 0.22 g of product.

The above prepared mesylate (0.22 g, 0.6 mmol) and sodium azide (0.12 g, 1.79 mmol) were combined with dimethylformamide (15 mL).
And heated at 60 ° C. for 1.5 hours, then diluted with brine (50 mL), extracted with ethyl acetate (100 mL), dried and evaporated. Ethyl 3-methyl-1-
0.11 g of (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylate was obtained; ESI mass spectral analysis m / z (relative intensity).
316 (M + H, 100).

Part F: 3-Methyl-1- (2-azidomethyl-4-methoxyphenyl)-
1H-pyrazole-5-carboxylic acid: ethanol (2 mL) and water (2 mL)
3-methyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-pyrazole-5-carboxylate (0.11 g, 0.35 mmol)
Stir at 45 ° C. with 50% sodium hydroxide (3 drops) followed by TLC (1: 1).
(Hexane: ethyl acetate). When all the ester had been consumed, the reaction was cooled, diluted with brine and washed with ethyl ether (25 mL). 1 water layer
Acidified with N hydrochloric acid (pH = 1), extracted with ethyl acetate (2 × 30 mL), dried and evaporated. 3-methyl-1- (2-azidomethyl-4-methoxyphenyl)
1H-pyrazole-5-carboxylic acid (0.06 g) was obtained; ESI mass spectral analysis m / z (relative intensity) 285 (M + H, 100).

Part G: 3-Methyl-1- (2-azidomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4- (2-N-t-butylsulfamido) phenyl) phenyl) carboxamide: 3-methyl-1- (2-azidomethyl-4-) in dichloromethane (5 mL). Methoxyphenyl) -1H-pyrazole-5-
The carboxylic acid (0.60 g, 0.21 mmol) was cooled to 0 ° C. and oxalyl chloride (0.21 mL of a 2M solution in dichloromethane) and dimethylformamide (
1 drop). The reaction was completed within one hour, which was evaporated and pumped to remove residual HCl. 0.17 g of acid chloride was obtained.

The acid chloride prepared above in dichloromethane (3 mL) (0.17 g, 0
. 50 mmol) in 4- (2-N-tert) in dichloromethane (15 mL).
Butylsulfonamido) phenylaniline (0.15 g, 0.51 mmol),
An ice-cold solution of pyridine (0.39 g, 4.4 mmol) and 4,4-dimethylaminopyridine (0.09 g, 0.7 mmol) was added dropwise. 18 reactants
Warmed to ambient temperature over time, then evaporated, dissolved in ethyl acetate (30 mL), washed with 1N hydrochloric acid (20 mL) and dried. Flash chromatography on silica gel eluting with a hexane: ethyl acetate gradient of 2: 1 to 1: 1 gave 3-methyl-1- (2-azidomethyl-4-methoxyphenyl)-.
0.09 g of 1H-pyrazole-5- (N- (4- (2-N-tert-butylsulfamido) phenyl) phenyl) carboxamide was obtained; ESI mass spectrometry m / z (relative intensity) 572. (M + H, 100).

Part H: 3-Methyl-1- (2-aminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (2'-sulfamide- [l, l ']-biphen-4-yl)) carboxamide.TFA: 3-methyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-Nt-
Butylsulfamide- [1,1 ′]-biphen-4-yl)) carboxamide (0.09 g, 0.16 mmol) was treated with tin chloride (0.09 g, 0.16 mmol) in methanol (10 mL).
II) Stirred with dihydrate (0.11 g, 0.47 mmol). TLC
When the reaction was complete with (1: 1 hexane: ethyl acetate), it was evaporated to give 0.39 g of a crude mixture of aminomethyl product and tin salt. This material was heated at reflux for 45 minutes in trifluoroacetic acid (10 mL) and then evaporated. The residue was partitioned between 1 N sodium hydroxide (30 mL) and ethyl acetate (30 mL). The ethyl acetate solution was dried and evaporated to give 0.04 g of crude product. This material was washed on a reverse phase C18 (6 nm) column with water containing 0.05% trifluoroacetic acid:
Further purification by HPLC, utilizing a gradient elution with a mixture of acetonitrile, afforded 0.010 g of the title compound; mp 184.3 ° C .; HRMS (M
+ H) ⁺ Calculated m / z: 492.170551, found m / z: 492.171 712.

Example 2 5-Methyl-1- (2-aminoethyl-4-methoxyphenyl) -1H-pyrazole-3- (N- (2′-sulfamide- [1,1 ′]-biphene) 4-yl)) carboxamide, trifluoroacetate Ethyl 5-methyl-1- (2-hydroxymethyl-4-methoxyphenyl) -1H-pyrazole-3-carboxy which is the regioisomeric acid prepared in Example 1 The rate (0.14 g, 0.48 mmol) was converted to the azidomethyl analog in a manner similar to that described in Example 1 and coupled with 4- (2-N-tertbutylsulfonamido) phenylaniline. , 5-Methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-3- (N- (4- (2
-Sulfamide) phenyl) phenyl) carboxamide. The final product was further purified by HPLC on a reversed phase C18 (6.0 nm) column utilizing a gradient elution with a mixture of water: acetonitrile containing 0.05% trifluoroacetic acid; HRMS (M + H) ⁺ Calculated value m / z: 492.170551, measured value m / z: 492.169327.

Example 3 3-Methyl-1- (2-N, N-dimethylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-N-methylsulfamide) − [1,
1 ′]-biphen-4-yl)) carboxamide, trifluoroacetate 3-methyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- ( 2′-Nt-butylsulfamide-
[1,1 ']-biphen-4-yl)) carboxamide (0.09 g, 0.1
6 mmol) was added to tin (II) chloride dihydrate (0.1 mL) in methanol (10 mL).
11 g, 0.47 mmol). When the reaction was completed by TLC (1: 1 hexane: ethyl acetate), it was evaporated to give 0.39 g of a crude mixture of aminomethyl product and tin salt. The crude reduction product prepared above (0
. 1 g, 0.20 mmol) with methyl iodide (0.2 mL) at ambient temperature and potassium bicarbonate (solids, 0.2 g) in methanol (4 mL)
And stirred at ambient temperature. After 18 hours, the reaction was evaporated and chloroform (30
mL), filtered and evaporated again to give 0.28 g of crude product.

The material obtained above was heated at reflux for 45 minutes in trifluoroacetic acid (10 mL) and then evaporated. The residue was partitioned between 1 N sodium hydroxide (30 mL) and ethyl acetate (30 mL). The ethyl acetate solution was dried and evaporated to give a crude product. This material was purified on a reverse phase C18 (6 nm) column using a gradient elution with a mixture of water: acetonitrile containing 0.05% trifluoroacetic acid by HP.
Further purification by LC provided the title compound; mp 114.5 ° C; HRMS (
M + H) ⁺ calculated m / z: 534.21752, found m / z: 534.21 8000.

Example 4 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1] -Bifen-4-yl)) carboxamide, trifluoroacetate Part A: 3-Trifluoromethyl-1- (2-carboxy-4-methoxyphenyl) -5- (furan-2-yl) -1H -Pyrazole: acetic acid (150 mL)
Of crude 2-carboxy-4-methoxyphenylhydrazine (8.88 g) prepared in Example 1 and 4,4,4-trifluoro-1- (2-furyl) -1.
, 3-butanedione (7.4 g, 135.9 mmol) was heated at 100 <0> C for 4 hours. The hot reaction mixture was evaporated and the residue was washed with water (150 mL) and chloroform (
(150 mL) in a two-phase mixture. The layers were filtered, separated and the solid precipitate was further washed several times with chloroform (3 × 50 mL), the chloroform layer and the washes were combined, dried and evaporated. 3-trifluoromethyl-1- (2-carboxy-
4-methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole 3.5
5 g were obtained; ESI (-ve) mass spectrum analysis m / z (relative intensity) 351
(MH, 100).

Part B: 3-Trifluoromethyl-1- (2-hydroxymethyl-4-methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole: 3-tri in tetrahydrofuran (100 mL) Fluoromethyl-1- (2-carboxy-4
-Methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole (3.5
5 g, 10.1 mmol) was cooled to 0 ° C. and then N-methylmorpholine (
1.02 g, 10.1 mmol) and isobutyl chloroformate (1.38)
g, 10.1 mmol). The reaction mixture was stirred at 0 ° C. for 30 minutes, filtered and immediately added to a cold solution of sodium borohydride (1.15 g, 30.2 mmol) in water (50 mL) and tetrahydrofuran (50 mL). The reaction mixture was evaporated and partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL), then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried, evaporated and then purified by flash chromatography using 4: 1 hexane: ethyl acetate as eluent. 1.5 g of 3-trifluoromethyl-1- (2-hydroxymethyl-4-methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole were obtained; ESI mass spectral analysis m / z ( Relative intensity) 339 (M + H, 100).

Part C: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole: 3-trifluoromethyl-1- ( 2-Hydroxymethyl-4-methoxyphenyl) -5- (furan-2-yl) -1H-pyrazole (1.5 g, 4.44 mmol) and triethylamine (1.79 g, 17.7 mmol) in cold chloroform (50 mL). To the solution was added a solution of methanesulfonyl chloride (2.03 g, 17.7 mmol) in chloroform (10 mL). The reaction was completed in 4 hours. It was evaporated, dissolved in ethyl acetate (100 mL), and washed with cold 5% NaHS0 ₄ (50mL) and cold saturated Na HCO ₃ (50mL). The organic layer was dried and evaporated to give mesylate. 1 g was obtained, which was used immediately in the next step; ESI mass spectral analysis m /
z (relative intensity) 417 (M + H, 100).

The mesylate prepared above (2.1 g) in dimethylformamide (40 mL)
5.05 mmol) and sodium azide (0.98 g, 15.1 mmol)
)) Was heated at 60 ° C. for 2 hours. The reaction mixture was cooled and brine (100 m
L) and extracted with ethyl acetate (100 mL). Extract the ethyl acetate with water (
5 × 50 mL), then dried and evaporated. 3-trifluoromethyl-
1- (2-azidomethyl-4-methoxyphenyl) -5- (furan-2-yl)
1.43 g of -1H-pyrazole were obtained; ESI mass spectral analysis, m / z (
Relative intensity) 364 (M + H, 100).

Part D: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid: 3 in acetone (60 mL)
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -5
To 1.43 g of-(furan-2-yl) -1H-pyrazole (3.9 mmol),
Potassium permanganate (5: 0 g, 27.5 mmol) in water (60 mL) was added. The reaction was heated at 60 ° C. for 3 hours, then cooled to ambient temperature and isopropyl alcohol (60 mL) was added. The mixture was stirred for 18 hours, then filtered through a pad of Celite® and washed with copious amounts of isopropyl alcohol. The filtrates were combined and evaporated, the residue was dissolved in 1N NaOH (50 mL) and washed with ethyl ether (2 × 50 mL). The base layer was acidified with 1N HCl (75 mL) and solid NaCl was added. The suspension was extracted with EtOAc (3 × 100 mL) and the extracts were dried and evaporated. 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid 0.91
g; ESI (-ve) mass spectral analysis m / z (relative intensity) 340 (
MH, 100).

Part E: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloride: dichloromethane (
3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (1.09 g, 3.2 mmol) in 50 mL).
l) is treated with 3.2 m of a 2M solution of reagents and a catalytic amount of DMF (3 drops) in dichloromethane.
From L, the mixture was stirred at 0 ° C. with oxalyl chloride. The reaction was completed in 3 hours, then evaporated and pumped to remove residual reagent. 3-trifluoromethyl-1-
1.04 g (2.9 mmol) of (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloride was obtained.

Part F: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (2-N-t
tertbutylsulfamide- [1,1] -biphen-4-yl)) carboxamide: 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl prepared above in dichloromethane (10 mL). ) -1H-Pyrazole-5
Carboxylic acid chloride (0.52 g, 1.45 mmol) was added to dichloromethane (
2-Fluoro-4- (2-N-tertbutylsulfonamide) in 30 mL)
Phenylaniline (0.56 g, 1.74 mmol), pyridine (1.14 g,
14.5 mmol) and 4,4-dimethylaminopyridine (0.21 g, 1.
(74 mmol) was added dropwise. The reaction was warmed to ambient temperature over 18 hours, then evaporated, dissolved in ethyl acetate (100 mL), and added 1N hydrochloric acid (
(50 mL) and dried. Silica gel flash chromatography, eluting with 4: 1 hexane: ethyl acetate, gave 3-trifluoromethyl-1-.
(2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N-
0.28 g of (2-fluoro-4- (2-N-tertbutylsulfamidophenyl) phenyl) carboxamide was obtained; ESI (-ve) mass spectrum analysis m / z (relative intensity) 644 (M- H, 100).

Part G: 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphen-1-yl) -1H-pyrazole-5- (N- (2-fluoro-4- (2
-Sulfamide- [1,1] -biphen-4-yl)) carboxamide.TF
A: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (2-N-tertbutylsulfamide phenyl)) Phenyl) carboxamide (0.28 g, 0.4
3 mmol) and tin (II) chloride dihydrate (0.29 g, 1.3 mmol)
Was stirred in methanol (30 mL) for 18 hours. The reaction was evaporated and the reduced product (0.60 g) was used without further treatment in the next step.

The product prepared above was refluxed in trifluoroacetic acid (20 mL) for 30 minutes,
Then evaporated. The residue was suspended in 1N NaOH (30 mL) and EtOAc (3
× 50 mL), dried and evaporated. This material was further purified by HPLC on a reversed phase C18 (6 nm) column utilizing a gradient of water: acetonitrile with 0.05% trifluoroacetic acid to give the title compound; mp 103.2 ° C. ; ESIESI mass spectrum analysis m / z (relative intensity) 5
64.2 (M + H, 100).

Example 5 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1 ′, 1] -Bifen-4-yl)) carboxamide, trifluoroacetate Part A: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl)-) 1H-pyrazole-5- ( N- (2-fluoro-4- (2-methylsulfonylphenyl) phenyl) carboxamide: dichloromethane (10 m
3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid prepared in Example 4 in L) (0.52 g,
1.45 mmol) was added to 2-fluoro-4- (2-chloro-4- (30 mL) in dichloromethane (30 mL).
2-methylsulfonylphenyl) aniline (0.52 g, 1.74 mmol),
It was added dropwise to an ice-cold solution of pyridine (1.14 g, 14.5 mmol) and 4,4-dimethylaminopyridine (0.21 g, 1.74 mmol). The reaction was warmed to ambient temperature for 18 hours, then evaporated and ethyl acetate (100 mL
), Washed with 1N hydrochloric acid (50 mL) and dried. Silica gel flash chromatography, eluting with a gradient of 5: 1 to 1: 1 hexane: ethyl acetate, gave 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5. -(N- (2-fluoro-4
0.46 g of-(2-methylsulfonylphenyl) phenyl) carboxamide were obtained; ESI mass spectral analysis m / z (relative intensity) 587 (M + H, 100
).

Part B: 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1, 1] -Bifen-4-yl)) carboxamide.TFA: 3-
Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H
-Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1
] -Bifen-4-yl)) carboxamide (0.46 g, 0.78 mmol
) And tin (II) chloride dihydrate (0.53 g, 2.35 mmol) were stirred in methanol (25 mL) for 18 hours. The reaction was evaporated and the residue was washed with 1N NaO
Suspended in H (50 mL), extracted with EtOAc (3 × 100 mL), dried and evaporated to give 0.29 g of crude product. This material was further purified by HPLC on a reverse phase C18 (6 nm) column using a gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid to give the title compound; mp10
1.5 ° C .; ESI mass spectral analysis m / z (relative intensity) 563 (M + H, 1
00).

Example 6 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-Pyrazole-5- (N- (2'-methylsulfonyl- [1,1] -biphen-4-yl)) carboxamide, trifluoroacetate Part A: 3-Trifluoromethyl-1- (2 -Azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,
1] -Bifen-4-yl)) carboxamide: 3-trifluoromethyl-1
Treatment of-(2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloride and 4- (2-methylsulfonylphenyl) aniline by the method described in Part A of Example 5 gives 3 -Trifluoromethyl-1- (
2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (
4- (2-Methylsulfonylphenyl) phenyl) carboxamide was obtained.

Part B: 3-Trifluoromethyl-1- {2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-methylsulfonyl- [1,
1] -Bifen-4-yl)) carboxamide.TFA: 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-
Treatment of 5- (N- (4- (2-methylsulfonylphenyl) phenyl) carboxamide in the same manner as Part B of Example 5 afforded the title compound; HRMS (
M + H) ⁺ calculated m / z: 545.147037, found m / z: 545.14 5700.

Example 7 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-Pyrazole-5- (N- (2'-sulfamide- [1,1] -biphen-4-yl)) carboxamide, trifluoroacetate Part A: 3-Trifluoromethyl-1- (2- Azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-N-tertbutylsulfamide- [1,1] -biphen-4-yl)) carboxamide: 3-trifluoro Methyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloride and 4- (2-N-tertbutylsulfonamido) phenylaniline were described in Example 4, Part F. Process in the way
3-trifluoromethyl-1- (2-amidomethyl-4-methoxyphenyl)-
1H-Pyrazole-5- (N- (4- (2-N-tertbutylsulfamidophenyl) phenyl) carboxamide was obtained.

Part B: 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphen-1-yl) -1H-pyrazole-5- (N- (2′-sulfamide- [
1.1] -Bifen-4-yl)) carboxamide.TFA: 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4- ( Treatment of 2-N-tertbutylsulfamidophenyl) phenyl) carboxamide as described in Part G of Example 4 gave the title compound; LRMS (M + H) ⁺ : m / z 546.2.

Example 8 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl)
Carboxamide TFA Part A: 5- (furan-2-yl) -3-trifluoromethyl-1- (2-
Carboxy-4-methoxyphenyl) -1H-pyrazole: concentrated HCl (300
3-methoxy-6-aminobenzoic acid (23 g, 138 mmol) in
C. and cooled to NaNO ₂ (11.4 g, 165 mmol) in H ₂ O (50 mL).
l) was added dropwise while keeping the reaction temperature below 10 ° C. The reaction was stirred at <10 ° C. for 1 hour, then SCl ₂ .H ₂ O (92.3) in concentrated HCl (125 mL).
g, 413 mmol) were added dropwise. The reaction was warmed to ambient temperature and stirred for 3 hours. The precipitate was filtered, air-dried and then heated in a vacuum oven for 18 hours. 71.4 g of 3-methoxy-6-hydrazinobenzoic acid of tin (II) salt were obtained.

Heat the above prepared hydrazine (71.4 g) in acetic acid (800 mL) at 45 ° C. until dissolved, then 4,4,4-trifluoromethyl-1- (2-furyl) -1. , 3-butanedione (28.42 g, 138 mmol) was added and the mixture was heated at reflux for 2.5 hours. The reaction was cooled and evaporated to dryness. The residue was partitioned between H ₂ O (4 00mL) and CHCl ₃ (400mL), stirred for 30 minutes. The biphasic mixture was filtered, the layers were separated, the organic layer was dried (Na ₂ SO ₄ ) and evaporated,
49.4 g of 5- (furan-2-yl) -3-trifluoromethyl-1- (2-carboxyl-4-methoxyphenyl) -1H-pyrazole were obtained; LRMS (
^{ES-) M -: 351m / z} .

Part B: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid: THF at 0 ° C. (600 mL)
5- (furan-2-yl) -3-trifluoromethyl-1- (2-carboxyl-4-methoxyphenyl) -1H-pyrazole in the solution (49.4 g, 140.3 m)
mol) were added N-methylmorpholine (14.9 g, 147 mmol) and isobutyl chloroformate (20.1 g, 147.3 mmol).
After 3 hours at 0 ° C., the reaction mixture was filtered to a solution of NaBH ₄ (10.6 g, 280 mmol) in H ₂ O: THF (200 mL: 200 mL) at 0 ° C. After 18 hours, the reaction was quenched with 1N HCl (500 mL), then the THF was removed under vacuum. The residual aqueous suspension was saturated with solid NaCl and extracted with EtOAc,
Dried (Na ₂ SO ₄ ) and evaporated. The crude product was recrystallized from 1-chlorobutane to give 16.8 g of benzyl alcohol product. The mother liquor was applied to a column of flash SiO ₂ (50.0 g) and eluted with 2: 1 hexane: EtOAc to give 8.7 g of the benzyl alcohol product; LRMSES4- (M + H) ⁺ : 339 m / z.

The benzyl alcohol product prepared above (8 in CH ₂ Cl ₂ (200 mL)
. 7 g, 25.1 mmol) and Et ₃ N (3.1 g, 30.9 mmol) were cooled to 0 ° C. Methanesulfonyl chloride (3.5 mL) in CH ₂ Cl ₂ (10 mL)
g, 30.9 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for 3 hours. NaHS0 ₄ 5% solution of (200 mL) was added and the organic layer was separated, dried and evaporated to give the mesylate 10.25 g.

The mesylate obtained above in DMF (100 mL) (10.25 g, 24.
6 mmol) and NaN ₃ (4.8 g, 73.8 mmol) were stirred at ambient temperature for 18 hours. The reaction was diluted with brine (500 mL) and extracted with EtOAc,
The extract was washed with _{H 2 0 (5 × 150mL)} . Dry the EtOAc layer (Na ₂ S
0 _4), and evaporated to give the azidomethyl compound 8.16; LRMS ES ⁺ (M ⁺
H) ^<+> : 364 m / z.

Azidomethyl compound (23 g, 63.4 mmol) in acetone (400 mL)
) Was heated at 60 ° C., then KMnO ₄ (50 g, 31) in H ₂ O (300 mL).
7 mmol) was added. After the addition was complete, the reaction was heated for 1.5 hours. The cooled reaction was filtered through a pad of Celite® and evaporated. Water layer is 1N N
Basified with aOH (200 mL), washed with Et ₂ O (3 ×), then acidified with concentrated HCl, saturated with solid NaCl, and extracted with EtOAc (3 ×). Et
The OAc layer was dried and evaporated to give 15.1 g of 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid. ^{LRMS ES - (M-H)} -: 340m / z.

Part C: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxypyrrolidino) phenyl) carboxamide: 0 3- trifluoromethyl prepared above in CH ₂ Cl ₂ to at ° C.-1-(2-azidomethyl-4-methoxyphenyl)-1H-
Pyrazole-5-carboxylic acid _{(0.44g, 1.29mmol), CH 2} Cl 2 (2 eq, 1.29 mL) and 2M solution of oxalyl chloride in added followed by DMF
Was added. The ice bath was removed and the reaction was stirred for 3 hours and then evaporated. The obtained acid chloride was converted to N- (4-aminobenzoyl) pyrrolidine (0.32 g, 1.
68 mmol) and DMAP (0.47 g, 3.87 mmol) to give C
Dissolved in H ₂ Cl ₂ (20 mL). The reaction was stirred for 18 hours and then evaporated,
Dissolved in tOAc. The EtOAc layer was washed with 1N HCl and brine, dried (Na ₂ SO ₄ ) and evaporated. The product was further purified by column flash SiO ₂ eluting with 5 to 10% MeOH in CHCl ₃ (50 g), 3- tri fluoromethyl-1- (2-azidomethyl-4-methoxyphenyl)-1H- 0.24 g of pyrazole-5- (N- (4-N-carboxylpyrrolidino) phenyl) carboxamide was obtained; LRMS ES ⁺ (M + H) ⁺ : 514 m / z. Part D: 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxylpyrrolidino) phenyl) carboxamide TFA: MeOH 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxylpyrrolidino) phenyl) carboxamide (0.2 mL) in (20 mL). 24 g, 0.27 mmol
) And SnCl ₂ .2H ₂ O (0.24 g, 0.95 mmol) were treated with 18
Stirred for hours. The reaction was evaporated and dissolved in 1N NaOH. EtOA for base layer
Extracted with c, dried and evaporated. The crude product was further purified by HPLC on a reverse phase C18 (6 nm) column using a gradient elution with a mixture of water: acetonitrile containing 0.05% trifluoroacetic acid to give the title compound, 31.2 m
g. mp 117.5 ° C .; HRMS (M + H) ⁺ calculated m / z: 488.1 90950, found: 488.191005.

Example 9 M-benzylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxamide)
Piperidine TFA 3 prepared in Part B of Example 8 according to the procedure in Part C of Example 8.
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-pyrazole-5-carboxylic acid was coupled with N-benzylsulfonyl-4-aminopiperidine. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 98.3 ° C; HRMS (M + H) ⁺ calculated m / z: 5 52.189236 found: 552.188800.

Example 10 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-Pyrazole-5- (N- (5- (2'-sulfonamido) phenyl) pyrid-2-yl) carboxamide.TFA Following the procedure in Example 8 Part C, Part B of Example 8 3 prepared in
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-pyrazole-5-carboxylic acid was coupled with 2-amino-5-((2-Nt-butylsulfonamido) phenyl) pyridine. Part D of Example 8
The azidomethyl group was reduced to an aminomethyl group with SnCl ₂ .2H ₂ O by the method outlined in. The crude reduction product was then refluxed for 1 hour in trifluoroacetic acid (10 mL) to remove the t-butyl protecting group. The title compound was isolated by HPLC on a reversed phase C18 (6 nm) column using a gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid. Mp 86.6 ° C .; HRMS
(M + H) ⁺ calc. M / z: 547.1137535, found: 547.1382 00.

Example 11 3-Trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
1H-Pyrazole-5- (N- (5- (pyrid-2-yl)) pyrid-2-yl) carboxamide.TFA Following the procedure in Example 8, Part C, Prepared 3
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-Pyrazole-5-carboxylic acid was coupled with 2-amino-5- (pyrid-2-yl) pyridine. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 48.2 ° C; HRMS (M + H) ⁺ : 469.160 02 m / z.

Example 12 N-benzyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4
-Methoxyphenyl) -1H-pyrazole-5-carboxamido) piperidine.TFA Prepared in Example 8, Part B, following the procedure in Example 8, Part C.
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-pyrazole-5-carboxylic acid was coupled with N-benzyl-4-aminopiperidine. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 116.1 ° C .; HRMS (M + H) ⁺ : 488.2266 m / z.

Example 13 N-phenylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxamide)
Piperidine TFA 3 prepared in Part B of Example 8 according to the procedure in Part C of Example 8.
-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1
H-pyrazole-5-carboxylic acid was coupled with N-phenylsulfonyl-4-aminopiperidine. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 103 ° C .; HRMS (M + H) ⁺ : 538.1729 m / z.

Example 14 3-Trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (M- (3-fluoro-2′-methylsulfonyl- [1
, 1 ′]-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5 in parts A and B of Example 8. -By essentially the same method used for the carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-4-chlorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-chloro-6-aminobenzoic acid. Following the procedure in Part C of Example 8, this compound was converted to 2-fluoro-4-((2-methanesulfonyl)
Coupled with phenyl) aniline. The title compound was prepared and purified by the method outlined in Example 8, Part D; mp. 97.5 ° C; HRMS (M + H) ⁺ : 567.0891 m / z.

Example 15 3-Trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
1] -Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxyl in parts A and B of Example 8. By essentially the same method used for the acid, 3-trifluoromethyl-1-
(2-Azidomethyl-4-chlorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-chloro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. The method outlined in Part D of Example 8, was reduced azidomethyl group to aminomethyl group using SnCl ₂ · 2H ₂ 0. The crude reduction product was then dissolved in trifluoroacetic acid (10 mL) for 1 hour.
Reflux for hours to remove the t-butyl protecting group. The title compound was isolated by HPLC on a reverse phase C18 (6 nm) column using a gradient elution with 0.05% trifluoroacetic acid in water: acetonitrile; mp 128 ° C .; HRMS (
M + H) ^<+> : 568.0832 m / z.

Example 16 3-Trifluoromethyl-1- (2-aminomethyl-5-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ']-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5 in parts A and B of Example 8. -By essentially the same method used for the carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-5-chlorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 4-chloro-6-aminobenzoic acid. Following the procedure in Part C of Example 8, this compound was converted to 2-fluoro-4-((2-methanesulfonyl)
Coupled with phenyl) aniline. The title compound was prepared and purified by the method outlined in Example 8, Part D; mp 99.7 ° C; HRMS (M + H) ⁺ : 567.0859 m / z.

Example 17 3-Trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxyl in parts A and B of Example 8. By essentially the same method used for the acid, 3-trifluoromethyl-1-
(2-Azidomethyl-5-chlorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 4-chloro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to an aminomethyl group using SnCl ₂ .2H ₂ O according to the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 hour to remove the t-butyl protecting group. Reversed phase C18 (6 nm) using gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid
The title compound was isolated by HPLC on a column; mp 127.4 ° C .; HR
MS (M + H) ^<+> : 568.0837 m / z.

Example 18 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (H- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-Bifen-4-yl)) carboxamide.TFA In Example 8, parts A and B, 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole- By essentially the same method used for the 5-carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-methanesulfonyl) phenyl) aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Example 8, Part D; mp 125 ° C; HRMS (M + H) ⁺ : 551.1177 m / z.

Example 19 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5 in parts A and B of Example 8. By essentially the same method as used for the carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. Part D of Example 8
The azidomethyl group was reduced to an aminomethyl group using SnCl ₂ .2H ₂ O by the method outlined in. Then, the crude reduction product was treated with trifluoroacetic acid (10 mL).
Refluxed for 1 hour to remove the t-butyl protecting group. Reversed phase C18 (6n) using gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid
m) The title compound was isolated by HPLC on a column; mp 113.1 ° C .;
HRMS (M + H) ^<+> : 552.1112 m / z.

Example 20 3-Trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-Bifen-4-yl)) carboxamide.TFA In Example 8, parts A and B, 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole- By essentially the same method used for the 5-carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-5-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 4-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-methanesulfonyl) phenyl) aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 97.2 ° C .; HRMS (M + H)
4-: 551.1179 m / z.

Example 21 3-Trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ']-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-amidomethyl-4-methoxyphenyl) -1H-pyrazole-5 in parts A and B of Example 8. By essentially the same method as used for the carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-5-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 4-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. Part D of Example 8
The azidomethyl group was reduced to an aminomethyl group using SnCl ₂ .2H ₂ 0 by the method outlined in. Then, the crude reduction product was treated with trifluoroacetic acid (10 mL).
Refluxed for 1 hour to remove the t-butyl protecting group. Reversed phase C18 (6n) using gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid
m) The title compound was isolated by HPLC on a column; mp 101 ° C .; HR
MS (M + H) ^<+> : 552.1120 m / z.

Example 22 3-Trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5- (N- (3-fluoro-2′- Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide.TFA In Example 8, parts A and B, 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl)- By essentially the same method used for 1H-pyrazole-5-carboxylic acid, 3-trifluoroacetyl-1
-(2-azidomethyl-4,5-difluorophenyl) -1H-pyrazole-5
-The carboxylic acid was prepared from 3,4-difluoro-6-aminobenzoic acid. This compound was converted to 2-fluoro-4-((2-
Coupling with methanesulfonyl) phenyl) aniline. The title compound was prepared and purified by the method outlined in Example 8, Part D; HRMS (M + H) ⁺ : 569.1082 m / z.

Example 23 3-Trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5- (N- (3-fluoro-2′- Sulfamide-
[1,1 ′]-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole in parts A and B of Example 8. By essentially the same method used for the 5-carboxylic acid, 3-trifluoromethyl-1-
(2-azidomethyl-4,5-difluorophenyl) -1H-pyrazole-5
The carboxylic acid was prepared from 3,4-difluoro-6-aminobenzoic acid. Example 8
This compound was converted to 2-fluoro-4-((2-N
-T-butylsulfonamido) phenyl) aniline. The method outlined in Part D of Example 8, was reduced azidomethyl group to aminomethyl group using SnCl ₂ · 2H ₂ 0. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 hour to remove the t-butyl protecting group. The title compound was isolated by HPLC on a reverse phase C18 (6 nm) column using a gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid; mp1
18.7 ° C; HRMS (M + H) ⁺ : 570.1038 m / z.

Example 24 3-Trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (M- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-Bifen-4-yl)) carboxamide.TFA In Example 8, parts A and B, 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole- By essentially the same method used for the 5-carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-3-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 2-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-methanesulfonyl) phenyl) aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 105.1 ° C .; HRMS (M + H
) ⁺ : 551.1180 m / z.

Example 25 3-Trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-Bifen-4-yl)) carboxamide.TFA 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5 in parts A and B of Example 8. By essentially the same method as used for the carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-3-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 2-fluoro-6-aminobenzoic acid. This compound was coupled with 2-fluoro-4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. Part D of Example 8
The azidomethyl group was reduced to an aminomethyl group using SnCl ₂ .2H ₂ 0 by the method outlined in. Then, the crude reduction product was treated with trifluoroacetic acid (10 mL).
Refluxed for 1 hour to remove the t-butyl protecting group. Reversed phase C18 (6n) using gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid
m) The title compound was isolated by HPLC on a column; mp 115.8 ° C;
HRMS (M + H) ⁺ : 552.1111 m / z.

Example 26 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (2-methylsulfonyl- [1,1 ']
-Biphen-4-yl)) carboxamide.TFA of 3-trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid in parts A and B of Example In a manner essentially identical to that used for 3-trifluoromethyl-1-
(2-Azidomethyl-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid. Following the procedure in Part C of Example 8 this compound was converted to 4-((2-methanesulfonyl) phenyl)
Coupling with aniline. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 110.3 ° C .; HRMS (M + H) -1-: 53
3.1265 m / z.

Example 27 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-Pyrazole-5- (N- (4- (2-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide.TFA 3-Trifluoro in Parts A and B of Example 8 By essentially the same method as used for methyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid, 3-trifluoromethyl-1-
(2-Azidomethyl-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid. This compound was coupled with 4-((2-Nt-butylsulfonamido) phenyl) aniline according to the procedure in Part C of Example 8. The method outlined in Part D of Example 8, was reduced azidomethyl group to aminomethyl group using SnCl ₂ · 2H ₂ 0. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 hour to remove the t-butyl protecting group. The title compound was isolated by HPLC on a reversed phase C18 (6 nm) column using a gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid; mp 136.8 ° C .; HRMS (M +
H) ^<+> : 534.1227 m / z.

Example 28 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (N-((N'-methylsulfonyl) iminoyl) pyrrolidino)) phenyl) carboxamide-TFA Part A: 4-amino-N-((N'-methyl Sulfonyl) iminoyl) pyrrolidine: 4-nitrobenzonitrile (5.4 g, 36.5 mmol) in anhydrous methyl acetate (200 mL) and MeOH (20 mL) was cooled to 0 ° C. and treated with a stream of dry HCl gas for 1 hour. did. Stop the reaction safely and leave it in the refrigerator at 5 ° C for 24 hours.
I left it. The solvent was removed and the reaction was repeatedly evaporated with Et ₂ O (5 ×) to remove the last traces of free HCl. 28.6 g of imidate were obtained as the HCl salt. This material was dissolved in anhydrous MeOH (100 mL) and pyrrolidine (40.1
mmol, 2.85 g). The reaction was stirred for 18 hours and then evaporated to 1
Stir in N HCl (150 mL), remove insoluble material by filtration and then evaporate the HCl solution. The residue was dried by azeotropic removal of EtOH and H ₂ O to give 7.44 g of the amidine product; LRMS ES ⁺ (M + H) ⁺ : 220.1 m /
z.

The free base of amidine prepared above was formed by suspending the product in 1 N NaOH (250 mL) and extracting the suspension with CHCl ₃ (3 ×). This material was dried and evaporated to give 4.49g of product.

The amidine prepared above (14.2 mm) in CH ₂ Cl ₂ (100 mL) at 0 ° C.
ol) to 3.1 g of the free base was added DMAP (2.1 g) in CH ₂ Cl ₂ (25 mL).
, 17 mmol) followed by methanesulfonyl chloride (1.95 g, 17 mmol)
Was added. After 18 hours at ambient temperature, the reaction was quenched with 1N HCl (2 ×), 1N N
Washed with aOH and brine, dried and evaporated. 3.6 g of mesylated product
I got LRMS ES ^<+> (M + H) ^<+> : 298.1.

The above mesylated product (3.6 g, 12 mmol) in EtOH (100 mL)
l) and SnCl ₂ .2H ₂ O (8.12 g, 36 mmol) were heated at reflux for 2 hours. The solvent was removed and the residue was washed with 1N NaOH (150 mL) and CH ₂ Cl ₂ (
100 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 100 mL), dried (Na ₂ SO ₄ ) and evaporated to give 2.7 g of 4-amino-N-((N′-methylsulfonyl) iminoyl) pyrrolidine. LRMS ES ⁺ (M + H) ⁺ : 26
8.1 m / z.

Part B: 3-Trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl) -1H-pyrazole-5- (N- (4- (N-((N′-methylsulfonyl) )) Iminoyl) pyrrolidino)) phenyl) carboxamide.TPA: 3-Trifluoromethyl-1- (2-azidomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid in parts A and B of Example 8. According to essentially the same method as used for the above, 3-trifluoromethyl-1-
(2-Azidomethyl-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid. This compound was coupled with 4-amino-N- (N'-methylsulfonyl) iminoyl) pyrrolidine prepared in Example 28 Part A according to the procedure in Example 8 Part C. The title compound was prepared and purified by the method outlined in Example 8, Part D.
p138.4 ° C; HRMS (M + H) ⁺ : 553.1640 m / z.

Example 29 3-Trifluoromethyl-1- (2- (N-glycyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ′ -Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide.TF
A 3-Trifluoromethyl-1- (2- (N-glycyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1, 1 ']-biphen-4-yl)) carboxamide-TF
A: 3-Trifluoromethyl-1- (2-aminomethyl-) in DMF (3 mL)
4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ′
-Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide.TFA (prepared in Example 5, 0.15 g, 0.22 mmol), NB
oc glycine (0.039 g, 0.22 mmol) and HBTU (0.084
g, 0.22 mmol) was cooled to 0 ° C. and NMM (0.075 g, 0
. 75 mmol) was added. After 6 hours, the reaction was diluted with brine and extracted with EtOAc. The EtOAc layer was washed with 5% NaHSO ₄ and brine (5 ×), then dried (MgSO ₄ ) and evaporated to give 0.14 g of product; LRMS ES ⁺ (M + H) ⁺ : 720 .4 m / z.

The product from above was stirred in 5% TFA in CH ₂ Cl ₂ (20 mL) for 18 hours. The reaction was evaporated and H on a reverse phase C18 (6 nm) column using a gradient elution with water: acetonitrile containing 0.05% trifluoroacetic acid.
The product was purified by PLC to give 0.087 g of the title compound; mp92.
5 ° C; HRMS (M + H) ⁺ : 620.160000 m / z.

Example 30 3-Trifluoromethyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2
'-Methylsulfonyl- [1,1']-biphen-4-yl)) carboxamide 3-trifluoromethyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H- Pyrazole-5- (N- (3-fluoro-2
'- methylsulfonyl - [1,1'] - biphen-4-yl)) carboxyamide: CH ₂ Cl ₂ (10mL) solution of 3- trifluoromethyl-1- (2-Aminomethyl-4-methoxyphenyl ) -1H-Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide.TFA (prepared in Example 5, 0 A mixture of 0.15 g (0.22 mmol) and Et ₃ N (0.068 g, 0.66 mmol) was cooled to 0 ° C. and phenylacetyl chloride (0.22 mol in 1 mL CH ₂ Cl ₂ ) was added dropwise. Was. The reaction was completed in 3 hours. It was further diluted with CH ₂ Cl ₂ and washed with 1N HCl, dried and evaporated. The residue on 200g column of flash SiO ₂ 1: 1 hexanes: was further purified by HPLC eluting with EtOAc. Fractions (25 mL) were collected and the product was isolated in a 44-75 tube to give 0.086 g of the desired product; mp 179-181 ° C; HRMS (M + H) ⁺ : 681.1786 m / z,

Example 31 3- (Trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H
-Pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide.TFA 2- [5- (2-furyl) -3- (trifluoro Methyl) -1H-pyrazole-
1-yl] benzoic acid: 4,4,4-trifluoro-1- (2-furyl) -1,3
-Butanedione (2.4 mL, 16 mmol) was added to 2-hydrazinobenzoic acid (3.01 g, 16 mmol) in acetic acid (20 mL) and heated to reflux for 25 hours.
The reaction was cooled, diluted with EtOAc and extracted twice with water. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to a thick red paste (5.71 g,> 100%)
I got ¹ H NMR (CDCl ₃ ) δ 8.18 (dd, 1 H, J = 7.7, J
'= 1.8), 7.74 (td, 1H, J = 7.7, J' = 1.4), 7.65
(Td, 1H, J = 7.7, J '= 1.5), 7.50 (dd, 1H, J = 7.
3, J '= 1.1), 7.35 (m, 1H), 6.89 (s, 1H), 6.28
(M, 1H), 5.76 (d, 1H, J = 3.3).

2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazole-
1-yl] benzamide: 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoic acid (5.13 g, 16 mmol) in thionyl chloride (25 mL) Dissolve and heat to reflux for 2 hours. Excess thionyl chloride was evaporated and the resulting hydrochloric acid was placed under high vacuum. The acid chloride was then redissolved in CH ₂ Cl ₂ (25 mL) and cooled to 0 ° C. Concentrated aqueous NH ₃ (6 mL) was added in several portions over 30 minutes. The resulting mixture was stirred at 0 ° C. for 30 minutes,
Then it was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with _{CH 2 Cl 2 (3 ×)} . The organic layers were combined and extracted with 2M Na ₂ CO ₃ . The organic layer was Drying with MgSO _4, filtered and evaporated to give the desired product (4.76g, 93%). ¹ H NMR (CDCl ₃ ) δ 7.98 (dd, 1H, J = 7.3, J ′ = 2.2), 7.67 (m, 2H), 7.41 (m, 2H), 6. 96 (s, 1H);
28 (m, 1H), 5.89 (bs, 1H), 5.67 (d, 1H, J = 2.9)
).

2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazole-
1-yl] benzonitrile: 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzamide (6.73 g, 21 mmol)
) And triethylamine (5.8 mL, 42 mmol) in dry CH ₂ Cl ₂ (5
(5 mL) under argon and cooled to 0 ° C. CH ₂ Cl ₂ (15 mL)
Trichloroacetyl chloride in (2.7 mL, 24 mmol) was added dropwise over 30 minutes. The resulting solution was stirred at 0 ° C. for 20 minutes, then at room temperature for 65 minutes. The reaction was quenched with a small amount of water and then partitioned between 1 M HCl and CH ₂ Cl ₂ . The organic layer was removed, extracted with saturated NaHCO _3, then dried over Na ₂ S0 _4, filtered and evaporated to give the crude product (6.66 g). The crude product was chromatographed on silica gel (30-40% EtOAc / hexanes) to give a yellow solid (6.51 g,> 100%). ¹ H NMR (CDCl ₃ ) δ 7.79 (m, 2H), 7.64 (m, 2H), 7.39 (d, 1H, J = 1.8), 6.96 (s, 1H) , 6.37 (m, 1H), 6.04 (d
, 1H, J = 3.7).

2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazole-
1-yl] benzylamine: Cobalt chloride (1.76 g, 13.6 mmol) was added to 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazole- in DMF (40 mL). 1-yl] benzonitrile (4.12 g, 13.6 mm
ol) and sodium borohydride (1.03 g, 27.2 mmol). The reaction became black and warm. An ice bath was added and the reaction was stirred at 0 ° C. for 45 minutes, then at room temperature for 23 hours. Further, sodium borohydride (0.
25 g, 6.6 mmol) was added and the resulting mixture was stirred at room temperature for 6 hours. A room temperature water bath was added and the reaction was quenched with water (10 mL) for 10 minutes, then MeOH (20 mL), then 6M HCl (20 mL) for 15 minutes. The quenched reaction was stirred at room temperature for 16 hours, diluted with EtOAc, and extracted with water and 0.1 M HCl. The resulting emulsion was filtered through celite, and the organic layer was removed, dried over Na ₂ SO _4, filtered and evaporated to give the crude product (857 mg). The aqueous layers were combined and neutralized (pH 8) with solid Na ₂ SO ₃ (6.9 g). Addition of EtOAc resulted in another emulsion, which was filtered through celite. The organic layer was removed and the aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product (3.5
5g) was obtained. The two batches of crude product were combined and chromatographic purification on silica gel _{(0~10% MeOH / CHCl 3)} , to give the desired product (3.77g, 90%). ¹ H NMR (CDCl ₃ ) δ 7.59
(M, 2H), 7.38 (m, 2H), 7.33 (d, 1H, J = 7.3), 6
. 96 (s, 1H), 6.27 (m, 1H), 5.59 (d, 1H, J = 3.6
), 3.51 (s, 2H).

T-butyl 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] benzylcarbamate: triethylamine (2.6 mL,
18.7 mmol) and di-t-butyl dicarbonate (4.0 g, 18.4).
mmol) with 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzylamine (3.77 g, 1 mL) in THF (60 mL).
2.3. mmol) and stirred at room temperature for 17 hours. The reaction was concentrated, diluted with Et ₂ O, and extracted with water (2 ×). The aqueous layers were combined and extracted with Et ₂ 0. The organic layers were combined, dried over MgSO _4, filtered and evaporated to give the crude product (5.58 g). The crude product is chromatographed on silica gel (10-20% Et
OAc / hexanes), a waxy solid (3.82 g, 76%). ¹ H NMR (CDCl ₃ ) δ 7.57 (m, 2H), 7.43 (m, 2H), 7. 32 (d, 1H, J = 7.7), 6.95 (s, 1H), 6.28 (m, 1H)
5.66 (d, 1H, J = 3.3), 4.82 (bs, 1H), 4.01 (b
d, 2H, J = 6.2), 1.39 (s, 9H).

1- (2-([(t-butoxycarbonyl) amino] methyl) phenyl) -3
-(Trifluoromethyl) -1H-pyrazol-1-yl-5-carboxylic acid: t-
Butyl 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzylcarbamate (3.77 g, 9.2 mmol) was added to t-B.
Dissolved in uOH (60 mL). A 5% aqueous solution of NaH ₂ PO ₄ (40 mL) was added, followed by several portions of solid KMnO ₄ (5.86 g, 37 mmol) over 25 minutes. The resulting mixture was heated at 65 C for 40 minutes. Further KM
nO ₄ (1.39 g, 8.8 mmol) was added and the reaction continued to heat at 65 ° C. for 35 minutes. The reaction mixture was cooled, filtered through celite, and rinsed with celite using EtOH and acetone. Concentrate the filtrate to about half its original volume,
Treatment with aqueous sodium nitrite removed residual KMnO ₄ . The resulting mixture was extracted with EtOAc, the organic layer was removed, dried over Na ₂ SO ₄ , filtered and evaporated to give a crude product (1.50 g). The aqueous layer was cooled in ice and 1M HCl (6m
L) and extracted with EtOAc (containing a small amount of EtOH). Before separation,
Both layers were filtered through celite and treated with saturated NaHCO ₃ (1.5 mL). The aqueous layer was removed and extracted twice with EtOAc / EtOH. Solid NaCl was added both times to facilitate emulsion separation. The aqueous layer was extracted with CHCl ₃ , adjusted to pH 5 with 1M HCl, and extracted twice with CHCl ₃ / EtOH. The final six organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the product (2.43 g, 68%
2) was obtained. The first batch of product was chromatographed on silica gel (0-30% MeOH / CHCl ₃ ) to give the pure product (0.95 g, 27%). ¹ H NMR (DMSO) δ 7.34 (m, 4H), 7.16 (d, 1H), 6.81 (bs, 1H), 3.79 (bd, 2H), 1.32 (
s, 9H).

1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl)-
5- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) aminocarbonyl 3-3- (trifluoromethyl) pyrazole: oxalyl chloride (90
μl, 1.0 mmol) and DMF (2 drops) were added to 1 mL of CH ₂ Cl ₂ (5 mL).
-(2-([(t-butoxycarbonyl) amino] methyl) phenyl) -3- (
Trifluoromethyl) -1H-pyrazol-1-yl-5-carboxylic acid (200 m
g, 0.52 mmol) and the resulting solution was stirred for 90 minutes at room temperature. The resulting compound was briefly placed under high vacuum before the solvent was evaporated and redissolved in CH ₂ Cl ₂ (5 mL). Triethylamine (220 μl, 1.6 mmol), 4-amino-2′-methylsulfonyl- [1,1 ′]-biphenyl hydrogen chloride (177 mg)
, 0.62 mmol), 4-dimethylaminopyridine (20 mg, 0.16 mn)
ol). The resulting solution was stirred at room temperature for 23 hours and the reaction was cooled to ice cold 1M.
HCl, then with saturated NaHCO ₃ , the organic layer was dried over MgSO ₄ , filtered and evaporated to give a crude product (241 mg). The crude product was chromatographed on silica gel (30-40% EtOAc / hexanes) to give the desired product (
64 mg, 20%). ¹ H NMR (CDCl ₃ ) δ 8.21 (d, 1H
, J = 8.1), 7.58 (m, 5H), 7.35 (m, 8H), 7.18 (s)
, 1H), 4.16 (d, 2H, J = 5.8), 2.59 (s, 3H), 1.3
3 (s, 9H).

3- (Trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H
- pyrazol -5- (N- (2'- methylsulfonyl - [1,1 '] - biphen-4-yl)) carboxyamide tri fluoroalkyl acetate: TFA to _{(1mL), CH 2 Cl 2} (1mL) 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl) -5- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) aminocarbonyl]- 3- (Trifluoromethyl) pyrazole (64 mg, 0.10 mmol) was added and stirred at room temperature for 21 hours. The reaction was evaporated, was purified by reverse phase prep _{HPLC (15~70% MeCN / H 2} 0 / 0.5% TFA), to give the desired product (30mg, 46%). ¹ H NMR (DMSO) d 10.79 (s, 1H), 8.16 (bs, 2H), 8.04 (d, 1
H, J = 7.7), 7.77 (s, 1H), 7.71 (td, 1H, J = 5.8)
), 7.64 (m, 6H), 7.51 (m, 1H), 7.45 (d, 1H, J =
7.6), 7.34 (m, 3H), 3.79 (bm, 2H), 2.78 (s, 3
H). < ¹⁹ > F NMR (DMSO) d-61.22, -73.97. HRMS calcd _{C 25 H 22 N 4 O 3} F 3 S: 515.1365; Found, 515.1359.

Example 32 3-Trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]- Biphen-4-yl)) carboxamide.TFA 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl)-
5- (2 '-(t-butylamino) sulfonyl- [1,1']-biphen-4-
Yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole: Oxalyl chloride (90 μl, 1.0 mmol) and DMF (2 drops) were added to CH ₂ Cl ₂ (
1- (2-([(t-butoxycarbonyl) amino] methyl) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl-5-carboxylic acid (of Example 31) in 5 mL). (Part A, 200 mg, 0.52 mmol) and the resulting solution was stirred at room temperature for 95 minutes. The solvent was evaporated and the resulting compound was briefly placed under high vacuum before re-dissolving in CH ₂ Cl ₂ (5 mL).

Triethylamine (150 μl, 1.1 mmol), 4-amino-2 ′ (t-
Butylamino) sulfonyl- [l, l ']-biphenyl (190 mg, 0.62
mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol
) Was added and the resulting solution was stirred at room temperature for 23 hours. The reaction was extracted with dilute saline solution, ice-cold 1M HCl, and saturated NaHCO ₃ . The organic layer was dried over MgSO ₄ , filtered and evaporated to give a crude product (371 mg). The crude product was chromatographed on silica gel (30% EtOAc / hexanes) to give the desired product (74 mg, 21%). ¹ H NMR (CDCl ₃ ) δ 8.6
6. (bs, 1H), 8.15 (dd, 1H, J = 7.7, J ′ = 1.5),
45 (m, 10H), 7.25 (d, 1H, J = 6.9), 7.20 (s, 1H)
), 5.33 (bs, 1H), 4.15 (d, 2H, J = 5.8), 3.49 (
bs, 1H), 1.34 (s, 9H), 0.97 (s, 9H).

3-Trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]-biphen-4
- yl)) carboxyamide tri fluoroalkyl acetate: TFA (a _{2mL), CH 2 Cl 2 (} 1mL) in 1- [2 - (([( t- butoxycarbonyl) amino] methylation) phenyl) -5 -(2 '-(t-butylamino) sulfonyl- [1,1'
] -Bifen-4-yl)) aminocarbonyl] -3- (trifluoromethyl)
Pyrazole (74 mg, 0.11 mmol) was added and stirred at room temperature for 19 hours.
Additional TFA (2 mL) was added and the reaction continued to stir for 3 hours. The reaction was evaporated and purified by reverse-phase prep-HPLC (15-70% MeCN / HzO / 0.5% TFA) to give the desired product (41 mg, 59%). ¹ H NMR (DMSO) δ 10.75 (s, 1H), 8.17 (bs, 3H), 7.98 (dd.1)
H, J = 7.3), 7.76 (s, 1H), 7.57 (m, 7H), 7.44 (
d, 1H, J = 6.7), 7.32 (d, 2H, J = 8.8), 7.25 (m,
3H) 3.79 (bd, 2H, J = 5.1). ¹⁹ F NMR (DMSO) δ −
61.22, -73.99. HRMS calcd _{C 24 H 21 N 5 O 3} F 3 S: 516.1 317; Found, 516.1319.

Example 33 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-aminosulfonyl- [1,1 ']
-Biphen-4-yl)) carboxamide.TFA 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl)-
5- (3-fluoro-2 '-(t-butylamino) sulfonyl- [1,1']-
Biphen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole: Oxalyl chloride (300P.1,3.4Mmol) and DMF (3 drops), 1 in CH ₂ Cl ₂ (30 mL) -(2-[(t-butoxycarbonyl) amino] methylphenyl) -3- (trifluoromethyl) -1H-pyrazole-1-
Il-5-carboxylic acid (Part A of Example 31, 888 mg, 2.3 mmol)
And the resulting solution was stirred at room temperature for 65 minutes. The solvent is evaporated and CH ₂ Cl ₂ (
(30 mL) was briefly placed under high vacuum. 4-amino-3-fluoro-2 '-(t-butylamino) sulfonyl- [1,1']-
Biphenyl (890 mg, 2.8 mmol) and 4-dimethylaminopyridine (420 mg, 3.4 mmol) were added and the resulting solution was stirred at room temperature for 22 hours. The reaction was concentrated and chromatographed on silica gel (20-30%
EtOAc / hexanes). The fractions containing the product were combined, concentrated to half of the original volume, and then three times with ice-cold 1 M HCl, 1 M HCl at room temperature, saturated N
aHCOa, HCl in 2M, and extracted twice with saturated NaHCO _3. Na ₂ S
Dried 0 _4, filtered and evaporated to give the desired product (600mg, 38%).

3-Trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-aminosulfonyl- [1,1 ′]
-Biphen-4-yl)) carboxamide trifluoroacetate: TFA (9m
L) was treated with 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl) -5- (3-fluoro-2 ′-(t-butylamino) in CH ₂ Cl ₂ (3 mL). Sulfonyl- [1,1 ′]-biphen-4-yl)) aminocarbonyl]-
3- (Trifluoromethyl) pyrazole (600 mg, 0.87 mmol) was added and stirred at room temperature for 18 hours. The reaction was evaporated and reversed phase preparative HPLC (10-70).
% MeCN / H ₂ was purified by 0 / 0.5% TFA), to give the impure product (349m g). This material was purified by re-reverse phase _{HPLC (5~70% MeCN / H 2} O / 0 .5% TFA), to give the pure product (162mg, 35%). All impure fractions containing the product were combined and reverse phase HPLC (20-60% Me
Purification by CN / H ₂ 0 / 0.5% TFA) afforded further product (119 mg, 26%). ¹ H NMR (DMSO) δ 10.62 (s, 1H), 8.16 (bs, 2H), 7.98 (dd, 1H, J = 7.0, J ′ = 2.2), 7.
79 (s, 1H), 7.54 (m, 7H), 7.39 (s, 2H), 7.28 (
m, 2H), 7.15 (d, 1H, = 8.4), 3.78 (bm, 2H). ¹⁹ F
NMR (DMSO) [delta] 61.26, -74.29, -122.79. HR
MS calculated. _{C 24 H 20 N 5 O 3} F 4 S: 534.1223; Found, 534.12 16.

Example 34 3-Trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1, 1 ']
-Biphen-4-yl)) carboxamide.TFA 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl)-
5- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-
Yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole: Oxalyl chloride (320 [mu] l, 3.7 mmol) and DMF (4 drops), CH ₂ Cl ₂ (35 mL) solution of 1- (2 - ([ (T-butoxycarbonyl) amino] methyl)
Phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl-5-carboxylic acid (Part A of Example 31, 940 mg, 2.4 mmol) and the resulting solution was allowed to stand for 55 minutes at room temperature. Stirred. The solvent was evaporated and the compound obtained was placed briefly under high vacuum before redissolving in _{CH 2 C l 2 (20mL)} . 4-amino-3-fluoro-2′-methylsulfonyl- [1,1 ′]-biphenyl (750 mg,
_{2.8mmol) inCH 2 Cl 2 (15mL} ), 4- dimethylaminopyridine (
447 mg, 3.7 mmol) was added and the resulting solution was stirred at room temperature for 20 hours. The reaction was concentrated and chromatographed on silica gel (30-40% Et).
OAc / hexanes) and an impure product (802 mg),
It was purified on _{LC (10-70% MeCN / H 2} 0 / 0.5% TFA), to give pure raw Narubutsu (645mg, 42%).

3-Trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1,1 ′]
-Biphen-4-yl)) carboxamide trifluoroacetate: TFA (2m
L) was treated with 1- [2-(([(t-butoxycarbonyl) amino] methyl) phenyl) -5- (3-fluoro-2′-methylsulfonyl- [1,1) in CH ₂ Cl ₂ (2 mL). 1 ′]-Bifen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole (132 mg, 0.21 mmol) and stirred at room temperature for 5 hours. The reaction was evaporated, was purified by reverse phase prep _{HPLC (10-70% MeCN / H 2} 0 / 0.5% TFA), to give the desired product (80mg, 59%). ¹ H NMR (DMSO) δ 10.65, (s, 1H), 8.16 (bs, 3H), 8.05 (d, 1H, J = 6.6), 7.79 (s, 1H), 7.73
(Td, 1H, J = 6.2, J ′ = 1.5), 7.67 (dd, 1H, J = 7.
7, J ′ = 1.5), 7.54 (m, 5H), 7.35 (m, 2H), 7.19
(D, 1H, J = 8.0), 3.78 (bd, 2H, J = 5.5), 2.88 (
s, 3H). ¹⁹ F NMR (DMSO) δ-61.26, -74.11, -1
22.19. HRMS calculations. C25H ₂ 1N403F4S: 533.1217; Found, 533.1258.

Example 35 3-Trifluoromethyl-1- (2- (N- (glycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methyl Sulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide.TFA Following the procedure in Example 29, the title compound was converted to 1- [2-((aminomethyl) phenyl) -5- (3- Fluoro-2'-methylsulfonyl- [1,1 ']-
Bifen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole trifluoroacetate (prepared in Example 34) and prepared from N-Boc glycine; HRMS (M + H) ⁺ : 590 .1495 m / z.

Example 36 3-Trifluoromethyl-1- (2-((N- (N-methylglycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2 '-Methylsulfonyl- [1,1']-biphen-4-yl)) carboxamide.T
FA The title compound was converted to 1- [2-((aminomethyl) phenyl) -5- (3-fluoro-2′-methylsulfonyl- [1,1 ′]-according to the procedure of Example 29.
Bifen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole trifluoroacetate (prepared in Example 34) and prepared from N-Boc-N-methylglycine; HRMS (M + H) ⁺ : 604.1655 m / z.

Example 37 3-Trifluoromethyl-1- (2-carboxamidophenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1,1 ′] −
Bifen-4-yl)) carboxamidomethyl 2- [5- (2-furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoate: 2- [5- (2-furyl) -3- (Trifluoromethyl) -1H-pyrazol-1-yl] benzoic acid (Part A of Example 31
(6.5 g, 82 mmol) was dissolved in SOCl ₂ (130 mL) and heated to reflux for 2.5 hours. Excess SOCl ₂ was evaporated and the residual acid chloride was placed under high vacuum. The acid chloride was cooled to 0 ° C. and dry MeOH (130 mL) was added. The resulting solution was warmed up slowly and stirred at room temperature, then at room temperature for 22 hours. The solvent was evaporated and the crude product was chromatographed on silica gel (0-30% Et)
OAc / hexanes) to give the desired product (22.6 g, 82%). ¹ H N MR (CDCl ₃ ) δ 8.10 (dd, 1H, J = 7.3, J ′ = 1.9), 7.67 (m, 2H), 7.50 (dd, 1H, J = 7.7. J '= 1.4),
7.37 (s, 1H), 6.92 (s, 1H), 6.29 (m, 1H), 5.7
7 (d, 1H, J = 3.3), 3.62 (s, 3H).

1- (2-carbomethoxyphenyl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] -5-carboxylic acid: NaH ₂ P04 (320mL) and 5% aqueous solution of water (200 mL), a solution of methyl t-BuOH (470mL) 2-
[5- (2-Furyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzoate (23.7 g, 71 mmol) was added. The reaction was immersed in a water bath at room temperature and solid KMnO ₄ (55.8 g, 353 mmol) was added in several portions over 1 hour. The reaction was heated at 70 ° C. for 90 minutes, cooled and filtered through celite. Celite was rinsed with acetone and EtOAc. The filtrate was concentrated to remove most of the organics. And then extracted with EtOAc. The organic layer was extracted with saturated Na ₂ SO _3, dried over Na ₂ S0 _4, filtered, evaporated, and placed. The combined aqueous layers were neutralized to pH 6.5 with 2M HCl (100 mL), then EtOAc
(3x). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give a pure product (14.8 g, 67%). IH NMR (CDCl ₃ ) δ 8.10 (dd, 1H, J = 7.3, J ′ = 1.5), 7.64 (m, 2H),
7.42 (dd, 1H, J = 7.3, J ′ = 1.1), 7.31 (s, 1H),
3.69 (s, 3H).

1- [2-Carbomethoxyphenyl-5- (3-fluoro-2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) aminocarbonyl] -3- (trifluoromethyl ) Pyrazole: oxalyl chloride (2.9 mL, 33 mmol)
And DMF (10 drops), dried CH ₂ Cl ₂ (240 mL) solution of 1- (2-carbomethoxy-phenyl) -3- (trifluoromethyl)-1H-pyrazol-1-yl 3-5-carboxylic acid (7.0 g, 22 mmol) and the resulting solution was stirred at room temperature for 80 minutes. The solvent was evaporated and the resulting compound was washed with CH ₂ Cl ₂ (240 mL
) Was briefly placed under high vacuum before reconstitution. 4-amino-3-fluoro-2 '
-Methylsulfonyl- [1,1 ′]-biphenyl hydrochloride (7.4 g, 25 mmol
) And 4-dimethylaminopyridine (7.1 g, 58 mmol) were added, the resulting solution was stirred at room temperature for 67 hours, and the reaction was extracted with 1M HCl (2 ×) followed by saturated NaHCO ₃ . The organic layer was dried over MgSO _4, filtered and evaporated to give the crude product. The crude product is chromatographed on silica gel (30-50%
EtOAc / hexanes) to give the desired product (12.4 g, 99%). ¹ H NMR (CDCl ₃ ) δ 8.29 (t, 1H, J = 8.1), 8.21 (m, 2H), 8.11 (dd, 1H, J = 7.7, J ′ = 1) .5), 7.62 (m
, 5H), 7.30 (m, 2H), 7.14 (m, 2H), 3.77 (s, 3H)
), 2.69 (s, 3H).

1- [2-carboxyphenyl-5- (3-fluoro-2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) Pyrazole: 1 M LiOH (34 mL) was added to THF (285 m
1- [2-Carbomethoxyphenyl-5- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) aminocarbonyl] -3 in L)
-(Trifluoromethyl) pyrazole (12.0 g, 21 mmol) was added and stirred at room temperature for 26 hours. An additional 1 M LiOH (15 mL) was added and the reaction continued to stir for 18 hours. The resulting solution is heated at 35 ° C. for 2.5 hours, then
Heated at ° C for 18 hours. The reaction was cooled, concentrated and partitioned between Et ₂ 0 and water. The organic layer was extracted again with water (2x) and a small amount of white solid was considered product and added to the aqueous layer. Combine the aqueous layers, neutralize to pH 7 with 2M HCl (23 mL) and add Et.
Extracted with OAc. Further, it was added to a 2M aqueous HCl solution (2 mL), and this was added to EtO
Extracted twice with Ac. The EtOAc layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (10.3 g, 88%). ¹ H NMR (CDCl ₃ ) δ 8.21 (m, 4H), 7.75 (m, 1H), 7.60 (m, 4H),
7.29 (m, 3H), 7.13 (m, 2H), 2. . 70 (s, 3H).

3-Trifluoromethyl-1- (2-carboxamidophenyl) -1H-pyra
Zol-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-
Bifen-4-yl)) carboxamide: 1- [2-carboxyphenyl-5
-(3-Fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-i
)) Aminocarbonyl] -3- (trifluoromethyl) pyrazole (3.0 g)
5.5 mmol) with SOCl_Two(10 mL) and heated under reflux for 2 hours. Excess SOCl_TwoWas evaporated and the residual hydrochloric acid was placed under vacuum. Dry hydrochloric acid CH_TwoCl _Two , Cooled to 0 ° C and concentrated NH_ThreeThe aqueous solution (2.0 mL) was added for 20 minutes.
Added. The resulting mixture was stirred at room temperature for 18 hours. Reactant to CH_TwoCl_TwoAnd rare
And extracted with water. CHCl_Three, MeOH / CH_TwoCl_TwoAnd CH_TwoCl _Two Extracted. Combine all organics and add saturated NaHCO_Three(2x), 1M HC
1 and saturated NaCl. The organic layer is MgS0_Four, Filtered, evaporated and chromatographed on silica gel (30-75% EtOAc / hex).
Suns) to give the desired product (794 mg, 27%).¹H NMR (CDCl_Three , 400 MHz) δ 9.53 (bs, 1H), 8.25 (t, 1H, J = 8.
3), 8.20 (dd, 1H, J = 7.8, J '= 1.2), 7.75 (m, 1
H), 7.60 (m, 4H), 7.45 (m, 1H), 7.29 (dd, 1H,
J = 7.6, J '= 1.2), 7.20 (dd, 1H, J = -11.2, J- =
1.9), 7.12 (m, 2H), 6.13 (bs, 1H), 5.68 (bs,
1H), 2.67 (s, 3H).

Example 38 3-Trifluoromethyl-1- (2-cyanophenyl) -1H-pyrazole-
5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide 1- [2-cyanophenyl-5- (3-fluoro-2'- Methylsulfonyl-
[1,1 ′]-Biphen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole: 1- [2-carboxamidophenyl-5- (3-fluoro-2′-methylsulfonyl- [1, 1 ′]-Bifen-4-yl)) aminocarbonyl] -3- (trifluoromethyl) pyrazole (Example 36, 715 mg)
, 1.3 mmol) and triethylamine (360 μl, 2.6 mmol) were combined in dry CH ₂ Cl ₂ (10 mL) and cooled to 0 ° C. Trichloroacetyl chloride (160 μl, 1.4 mmol) was added over 5 minutes. The resulting solution was stirred at 0 ° C. for 30 minutes, then at room temperature for 2 hours. Further, triethylamine (200 μl, 1.4 mmol) was added. The reaction continued to stir at room temperature for 68 hours. Further, trichloroacetyl chloride (20 μl, 0.2 mmol) was added. After hiding for 2 hours, the reaction was quenched with water. The organic layer is removed and 1M HC
1 and saturated NaHCO ₃ . A small amount of saturated NaCl was added to. Emulsion destroyed. The organic layer was dried over Na ₂ S0 _4, filtered, evaporated, and chromatographic purification on silica gel (20-75% EtOAc / hexanes) to give the desired product (114 mg, 17%). ¹ H NMR (CDCl ₃ ) δ 8.25
(M, 2H), 8.09 (bs, 1H), 7.82 (m, 2H), 7.65 (m
, 4H), 7.35 (m, 2H), 7.20 (m, 2H), 2.72 (s, 3H)
).

Example 39 1- (2′-Aminomethylphenyl) -5-[[(2′-methylsulfonyl)
-3-Fluoro- [1,1 ′]-biphen-4-yl] aminocarbonyl] -tetrazole TFA salt Ethyl 1- (2-cyanophenyl) -5-tetrazolecarboxylate: CH ₂ Cl ₂ (250 mL) Anthranilonitrile (10.00 g) and E
Ethyl oxalyl chloride (9.92 mL) was added dropwise over 30 minutes to a solution of t ₃ N (13.21 mL). The reaction was stirred at room temperature under N ₂ for 3 hours. The reaction mixture was filtered, the filtrate was washed with water (2 × 150 mL) and brine (1 × 150 mL).
L), filtered through phase separation paper and evaporated. Residue is CH ₂ Cl ₂ 60 mL
And hexane (300 mL) was added. The solution was left at room temperature for one week. The precipitate is filtered, rinsed with hexane, dried under vacuum and 1- (2-cyanophenyl)-
17.74 g of oxoacetic acid ethyl ester was obtained.

A solution of triphenylphosphine (16.83 g) in CCl ₄ (100 mL) was stirred at 0 ° C. for 30 minutes. 1- (2-Cyanophenyl) -oxoacetic acid ethyl ester (7.00 g) in CCl ₄ (100 mL) was added and the reaction was stirred at reflux under N ₂ for 16 hours. The reaction was cooled to room temperature, the precipitate was filtered off, the filtrate was evaporated and dissolved in CH ₃ CN (300mL). Sodium azide (2.29 g) was added and the reaction was stirred at room temperature under N ₂ for 16 hours. The solvent was evaporated and dissolved in the residue EtOAc (100 mL). The organic solution was washed with water (2 × 100 mL) and brine (1 × 100 mL), dried over MgSO ₄ and evaporated. Things quality crude eluting with CH ₂ Cl ₂ and purified by silica gel chromatography to give the title compound ^{3.80g; LRMS (ES +) M} +: 244m / z 1- (2'- aminomethyl-phenyl) - 5-[[(2′-methylsulfonyl)
3-fluoro - [1,1 '] - biphen-4-yl] aminocarbonyl] - tetrazole: [(2'-methyl-aminosulfonyl) in anhydrous CH ₂ Cl ₂ (10 mL) -3-
To a solution of fluoro- [1.1 ′]-biphen-4-yl] amine (0.32 g) was added trimethylaluminum (2.12 mL, 2M in heptane) and the reaction was stirred at room temperature under N ₂ for 30 minutes did. Was added ethyl in anhydrous _{CH 2 Cl 2 (10mL) 1-} (2- cyanophenyl) -5- tetrazole carboxylate (0.28 g), the reaction was stirred for 64 hours at room temperature under N _2. The reaction was quenched with 5 drops of 1N HCl and diluted with CH ₂ Cl ₂ (30 mL). The organic solution was washed with water (2 x 25m
L) and brine (1 × 25 mL), filtered through phase separation paper,
Evaporated. The crude material was purified by silica gel chromatography, eluting with 10% EtOH / CH ₂ Cl ₂ and 1- (2′-cyanophenyl) -5-[[(2 ′
- methylsulfonyl) -3-fluoro - [1,1 '] - biphen-4-yl] amino carbonyl] - was obtained tetrazole ^{0.35g; LMRS (ES -) M} -: 4 61m / z.

Cobalt chloride (0.098 g) was treated with 1- (2′-cyanophenyl) -5-[[(2′-methylsulfonyl) -3-fluoro- [1,1 ′) in DMF (5 mL).
] -Bifen-4-yl] aminocarbonyl] -tetrazole (0.35 g) and sodium borohydride (0.072 g) and the reaction was stirred at room temperature for 16 hours. The resulting mixture was stirred at room temperature for 16 hours and 6M HCl (5 mL) was added over 5 minutes. The quenched reaction was stirred at room temperature for 3.5 hours,
Diluted with OAc and water. Filtering the resulting emulsion through Celite,
The organic layer was washed with 1N HCl, dried over Na ₂ SO ₄ , filtered and evaporated to give a crude product (100 mg). The aqueous layers were combined, neutralized with saturated NaHCO ₃ (pH 7) and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give a second batch of crude product. The two batches of crude product were combined and purified by reverse phase _{HPLC (10-90% MeCN / H 2} 0 / 0.5% TFA), to give the title compound 102mg as a TFA salt. LMRS (ES ⁺ ) M +: 467 m / z.

Example 40 1- (2′-aminomethylphenyl) -5-[(2′-aminosulfonyl- [
1,1 ′]-Bifen-4-yl) aminocarbonyl] -tetrazole.TFA The title compound was prepared in analog form as a TFA salt. LRMS (ES ⁺ ) M +: 468 m / z.

Example 41 1- [2- (Aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4 -Yl) aminocarbonyl] pyrazole / TFA methyl 3- (thiomethoxy) pyrazole-5-carboxylate: 2 in glacial acetic acid
00 mL of methyl 4,4-bis (thiomethoxy) -2-oxo-3-butenoate (
9.9 g, 48 mmol) and hydrazine monohydrate (2.6 mL, 53 mmol)
The mixture of 1) was stirred at 100 ° C. for 18 hours. The reaction was cooled and concentrated. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated. The solid residue was recrystallized from hexanes / ethyl acetate to give 6.0 g (73%) of the title compound. ¹ H NMR (CDCl ₃ ) δ
0 (broad, 1H), 6.74 (s, 1H), 3.88 (s, 3H), 2.4
8 (s, 3H).

Methyl 1- [2-formylphenyl] -3- (thiomethoxy) pyrazole-5
-Carboxylate: To a solution of methyl 3- (thiomethoxy) pyrazole-5-carboxylate (0.87 g, 5.05 mmol) in 20 mL of 1,4-dioxane, 2-formylphenylboronic acid (1.13 g, 7.0). 58 mmol), pyridine (0.82 mL, 10.1 mmol), milled 0.4 nm molecular sieve and cupric acetate (1.38 g, 7.58 mmol) were added. The flask was fitted with a drying tube and the mixture was allowed to warm to ambient temperature under an air atmosphere for 18 hours. The mixture was filtered through a pad of celite and concentrated. The residue was purified by flash chromatography to give 0.22 g (16%) of the title compound. ¹ H NMR (CDCl ₃ ) δ 9.66 (s, 1H), 8.02 (dd, 1H), 7.69 (td, 1H), 7.63 (t, 1H), 7.42 (d, 1H), 6.96 (s,
1H), 3.75 (s, 3H), 2.55 (s, 3H).

1-[(2- (hydroxymethyl) phenyl] -3-thiomethoxy-5-[(
2-Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole: methyl 1- in 15 mL of methanol at 0 ° C.
A solution of [2-formylphenyl] -3- (thiomethoxy) pyrazole-5-carboxylate (0.48 g, 1.74 mmol) was treated with sodium borohydride (
33 mg, 0.87 mmol). The cooling bath was removed and the reaction was stirred for 10 minutes, then quenched by elution with water. The reaction mixture was extracted with ethyl acetate, the organics were washed with brine, dried (MgSO _4), concentrated, approximately 2: 1 mixture of hydrate Rokishiesuteru and 7-membered lactone ring 0.41 g (85% ) Got.
This mixture was used without purification. (2-Fluoro-2 'in methylene chloride
-Methylsulfonyl- [1,1 ′]-biphen-4-yl) amine hydrogen chloride (0
. To a solution of 89 g / 2.94 mmol), trimethylaluminum (2.95 mL of a 2.0 M solution in hexanes, 5.89 mmol) was added dropwise. The solution was stirred until gas evolution ceased (15-20 minutes), then the hydroxyester / lactone mixture obtained above in methylene chloride (0.41 g, 1.47 m).
mol) was added. The resulting solution was stirred at reflux for 4 hours, then it was cooled and quenched by the dropwise addition of saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated, the organic layer was washed with water and brine, and dried (
MgSO _4), and concentrated. The solid residue was purified by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) to give 0.68 g (91%) of the title compound
I got LRMS (ES ⁺ ): 534.1 (M + Na) ⁺ 1-[(2- (bromomethyl) phenyl] -3-thiomethoxy-5-[(2-
Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)
Aminocarbonyl] pyrazole: 20 mL of 1-[(2- (hydroxymethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2
To a solution of '-methylsulfonyl- [1,1']-biphen-4-yl) aminocarbonyl] pyrazole (0.68 g, 1.3 mmol) was added carbon tetrabromide (1.06
g, 3.2 mmol) and triphenylphosphine (0.84 g, 3.2 mm).
ol) was added and the resulting solution was stirred at ambient temperature for 4 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO _4), and concentrated. The residue was purified by flash chromatography (eluting with 3: 1 hexanes / ethyl acetate) to give 0.60 g (81%) of the title compound.

1-[(2- (azidomethyl) phenyl] -3-thiomethoxy-5-[(2-
Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)
Aminocarbonyl] pyrazole: 1-[(2- (bromomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1] in 5 mL of N, N-dimethylformamide '] -Bifen-4-yl) aminocarbonyl] pyrazole (0.
Sodium azide (0.38 g, 5.42 g, -0.73 mmol).
85 mmol) was added. The mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO _4), concentrated and condensed to give the title compound 0.38 g (97%), which was used directly without purification. LRMS (ES ^<+> ): 559.1 (M + Na) ^<+> .

1- [2- (aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl Pyrazole, trifluoroacetate: 1-[(2- (azidomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′] in 10 mL of methanol)
-Biphen-4-yl) aminocarbonyl] pyrazole (0.38 g, 0.71
mmol), tin (II) chloride (0.80 g, 4.24 mmol) was added. The reaction mixture was stirred at reflux for 1 hour, then cooled to room temperature and diluted with ethyl acetate. The organics were washed with 5% aqueous sodium hydroxide and brine, dried (MgSO _4), and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, eluted with a H ₂ O / CH ₃ CN gradient containing 0.5% TFA) and lyophilized to give 230 mg (52%) of the title compound as a white powder. Was. LRMS (E
S ⁺ ): 511.1 (M + H) ⁺

Example 42 1- [2- (Aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole / TFA 1-[(2- (bromomethyl) phenyl] -3-methylsulfonyl-5- [ (
2-Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole: 1-[(2- (
Bromomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2
To a solution of '-methylsulfonyl- [1,1']-biphen-4-yl) aminocarbonyl] pyrazole (85 mg, 0.15 mmol) was added m-chloroperbenzoic acid (57-86% pure substance, 130 mg, -0). .5 mmol) was added. The resulting solution was stirred at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated to give 80 mg (88%) of the title compound, which was used without purification It was pure enough to do.

1-[(2- (azidomethyl) phenyl] -3-methylsulfonyl-5-[(
2-Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole: 1-[(in 1 mL of dimethylsulfoxide
2- (bromomethyl) phenyl] -3-methylsulfonyl-5-[(2-fluoro)-(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole (55 mg, 0 0.09 mmol) was added sodium azide (30 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO _4), and concentrated to give the title compound 50 mg (97%), which was used directly without Seisuru fine. LRMS (ES ⁺ ): 591.1 (M + Na) + 1- [2- (aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2′-methylsulfonyl-t1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole, trifluoroacetate: 1-[(2- (azidomethyl) phenyl] -3-in 4 mL of methanol. Methylsulfonyl-5-[(2
-Fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole (90 mg, 0.16 mmol) was added to a solution of tin (II) chloride (0.30 g, 1 .6 mmol) was added. The reaction mixture was stirred at reflux for 1 hour, then cooled to room temperature and diluted with ethyl acetate. 5% organic matter
Washed with aqueous sodium hydroxide and brine, dried (MgSO _4), and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with -H ₂ O / CH ₃ CN gradient with 0.5% TFA), and lyophilized to give the title compound 18m g (17%) as a white powder Obtained. LRMS (ES ⁺ ): 543.2 (M + H) ⁺

Example 43 1- [2- (Aminomethyl) phenyl] -5-[(2-fluoro)-(2′-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole.TFA 2-azidobenzyl alcohol: 50 mL of 2-aminobenzyl alcohol (12.0 g, 97.4 mmol) in trifluoroacetic acid at 0 ° C. To the solution of was added sodium nitrite (7.39 g, 107.2 mmol). The solution was stirred for 45 minutes, then sodium azide (6.33 g, 97.4 mmol) was added dropwise as a solution in water. The resulting mixture was stirred at 0 ° C. for 45 minutes, then carefully quenched by the addition of potassium carbonate. Dilute the reaction mixture with ethyl acetate,
Washed with brine, dried (MgSO _4), filtered through a pad of silica gel, and concentrated to give the title compound 10.5 g (72%), which was used without further purification. ¹ H NMR (CDCl ₃ ) δ 7.33 (m, 2H), 7.14 (m
, 2H), 4.59 (s, 2H), 2.69 (broads, 1H).

Methyl (2-azidophenyl) propionate: 2 in 200 mL of methylene chloride
-Azidobenzyl alcohol (15.66 g, 105.1 mmol) in solution
Propionic acid (7.1 mL, 115.6 mmol), dicyclohexylcarbodiimide (20.0 g, 110.3 mmol), 4-dimethylaminopyridine (1
. 93 g, 15.8 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was filtered, concentrated and the residue was flash chromatographed (1
: 1 hexanes / ethyl acetate) and 10.7 g (51%) of the title compound.
) Got. ¹ H NMR (CDCl ₃ ) δ 7.40 (m, 2H), 7.17 (m
, 2H), 5.20 (s, 2H), 2.92 (s, 1H).

Triazololactone: A solution of methyl (2-azidophenyl) propionate (10.7 g, 53.2 mmol) in 100 mL of toluene was stirred at 100 ° C. for 18 hours. The reaction was cooled, concentrated and the residue was purified by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) to give 1.4 g (13%) of the title compound.
). I got ¹ H NMR (CDCl ₃ ) δ 8.38 (s, 1H), 8.04 (
d, 1H), 7.63 (m, 1H), 7.54 (m, 2H), 5.16 (s.2)
H).

1-[(2- (hydroxymethyl) phenyl] -5-[(2-fluoro)-(
2′-Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole: (2-fluoro-2′-methylsulfonyl- [1,1 ′]-biphen-4-in methylene chloride Il) Amine hydrochloride (2.10 g, 6.96 mm
ol) in a solution of trimethylaluminum (2.0 M solution in hexanes, 20.8).
mL, 41.8 mmol) were added dropwise. The solution was stirred until gas evolution ceased (about 30 minutes), and then the triazololactone (1.40 g, 6.96 mmol) obtained above in methylene chloride was added as a solution. The resulting solution is
Stirred at reflux for an hour, then cooled and quenched by the dropwise addition of saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was washed with water and brine, dried (MgSO _4), and concentrated. The solid residue was purified by flash chromatography (eluting with 3: 1 ethyl acetate / hexanes) to give 1.0 g (31%) of the title compound. LRMS (ES ⁺ ): 467.2 (M + H) ⁺ 1-[(2- (bromomethyl) phenyl] -5-[(2-fluoro)-(2 '
-Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl
Triazole: 1-[(2- (hydroxymethyl) phenyl] -5-((2-fluoro)-(2′-methylsulfonyl- [1,1 ′] in 20 mL of methylene chloride.
-Biphen-4-yl) aminocarbonyl] triazole (0.80 g, 1.7
1 mmol), carbon tetrabromide (2.83 g, 8.55 mmol) and triphenylphosphine (2.24 g, 8.55 mmol) were added. The resulting solution was stirred at ambient temperature for 18 hours. The reaction was ethyl acetate dilution, in washing with water, brine, dried (MgSO _4), and concentrated. The residue was purified by Fish chromatography (elution with 1: 1 hexanes / ethyl acetate) to give 0.80 g of the title compound.
(89%). LRMS (ES ⁺ ): 529.1 / 531.1 (M + H) ⁺¹ -[(2- (azidomethyl) phenyl] -5-[(2-fluoro)-(2 '
-Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl
Triazole: 1-[(2- (bromomethyl) phenyl] -5-[(2-fluoro)-(2′-methylsulfonyl-) in 10 mL of N, N-dimethylformamide
[1,1′3-Bifen-4-yl) aminocarbonyl] triazole (0.2
5 g, 0.47 mmol) in a solution of azidonatriu (0.37 g, 5.6 mm).
ol). The mixture was stirred at 65 ° C. for 18 hours, then cooled and diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO _4), concentrated by condensation, to give the title compound 0.22 g (96%), which was used directly without purification. LRMS (ES ⁺ ): 514.2 (M + Na) ⁺ 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)-(2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole, trifluoroacetate: 1-[(2- (
Azidomethyl) phenyl] -5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole (0
. 22 g, 0.45 mmol) in a solution of 10% palladium-carbon catalyst (25 m
g) and concentrated HCl (0.04 mL, 0.45 mmol) were added. The reaction mixture was stirred at ambient temperature under 1 atm of hydrogen for 2 h, then filtered through a pad of Celite, concentrated and the residue was purified by preparative HPLC (C18 reverse phase column, H ₂ O / 0.5% TFA / (Eluted with a CH ₃ CN gradient) and lyophilized to give 26 mg (10%) of the title compound as a white powder. LRMS (ES ⁺ ): 466.2 (M + H) ⁺

Example 44 1- [2- (Aminomethyl) phenyl] -5-[(2-fluoro)-(2′-methylsulfonyl)-[1,1 ′]-biphen-4-yl) Aminocarbonyl] pyrazole / TFA methyl 1- [2-methylphenyl] pyrazole-5-carboxylate: methyl pyruvate (11.37 mL, 125.9 mmol) and dimethylformamide dimethyl acetal (16.72 mL, 125.9 mmol) The neat mixture was stirred at 80 ° C. for 24 hours. The mixture was cooled and concentrated. Residue (4.00
g, 25.45 mmol) was dissolved in 50 mL of glacial acetic acid, and then o-tolylhydrazine hydrochloride (4.44 g, 27.99 mmol) was added. This mixture is
Stirred at 00 ° C. for 18 hours, then cooled and concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (eluting with 2: 1 hexanes / ethyl acetate) to give 3.0 g (55%) of the title compound. ¹ H NMR (CDCl ₃ ) δ 7.70 (d, 1H), 7.4-7.2 (m, 4H), 7.00 (d, 1H), 3.71 (s, 3H), 2 .00 (s, 3H).

Methyl 1- [2- (bromomethyl) phenyl] pyrazole-5-carboxylate: methyl 1- [2-methylphenyl] pyrazole- in 20 mL of carbon tetrachloride
To a solution of 5-carboxylate (1.00 g, 4.62 mmol) was added N-bromosuccinimide (0.823 g, 4.62 mmol) and AIBN (76 mg).
, 0.46 mmol) was added and the mixture was stirred at 80 ° C. for 18 hours. The volatiles were removed and the residue was dissolved in ether, filtered through a pad of silica gel and concentrated to give 1.3 g (95%) of the title compound, which was used without further purification. LRMS (ES ⁺ ): 295.0 / 297.0 (M + H) ⁺ methyl 1- [2- (azidomethyl) phenyl] pyrazole-5-carboxylate: methyl 1- [2 in 10 mL of N, N-dimerformamide. -(Bromomethyl) phenyl] pyrazole-5-ruboxylate (1.30 g, 4.40 mmol)
To the solution of 1) was added sodium azide (2.86 g, 44.0 mmol). The mixture was stirred at ambient temperature for 48 hours, then diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO _4), and concentrated to give the title compound 0. 80 g (71%) were obtained, which was used without direct purification. LRMS (
ES ⁺ ): 280.1 (M + Na) ⁺¹ -[(2- (azidomethyl) phenyl] -5-[(2-fluoro)-(2 '
-Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl
Pizole: 20 mL of methylene chloride (2-fluoro-2'-methylsulfonyl- [
1,1 ′]-Bifen-4-yl) amine hydrogen chloride (0.94 g, 3.11 mm)
ol) in a solution of trimethylaluminum (4.67 M solution in hexanes, 4.67).
mL, 9.33 mmol) was added dropwise. The solution was stirred until gas evolution ceased (about 30 minutes) and then methyl 1- [2- (azidomethyl) phenyl] pyrazole-5-carboxylate (0.80 g, 3.11 mmol) in methylene chloride.
l) was obtained as a solution. The resulting solution was stirred at reflux for 18 hours, then cooled and quenched by the dropwise addition of saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate and the layers were separated. Wash the organic layer with water and brine,
Dried (MgSO _4), filtered through a pad of silica gel, and concentrated to give the title compound 1.0g (67%). LRMS (ES ⁺ ): 513.0 (M + Na) ⁺ 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)-(2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole, trifluoroacetate: 1-[(2- (azidomethyl) phenyl] -5-[(2-fluoro) in 20 mL of absolute ethanol -(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole (0.5
(0 g, 1.0 mmol) was added 10% palladium-carbon catalyst (50 mg) and concentrated HCl (0.085 mL, 1.0 mmol). The reaction mixture was stirred under 1 atmosphere of hydrogen at ambient temperature for 2 hours, then filtered through a pad of Celite,
Concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ 0 / CH3CN containing 0.5% TFA), lyophilized and purified with the title compound 6
0 mg (10%) was obtained as a white powder. LRMS (ES ⁺ ): 465.2 (M + H) ⁺

Example 45 1- [2- (Aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2'-pyrrolidinomethyl)-[1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole / TFA Part A: 2-Fluoro-4-((2'-tert- butyldimethylsilyloxy) phenyl) aniline: THF (80 mL) and aqueous Na ₂ CO ₃ (2M, 80 mL) solution of 2-formylphenyl boronic acid (5g, 33.3mmo
1) and 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol)
Was bubbled with nitrogen for 10 minutes. Pd (PPh ₃ ) ₄ (1.54 g, 1.
After addition of (33 mmol), the resulting mixture was refluxed for 4 hours under nitrogen. THF
The layers were separated and filtered through a pad of silica gel. The silica gel is washed with THF and a portion of NaBH ₄ (2.2 g, 29.1 mmol) is added to the combined filtrate containing 2-fluoro-4- (2′-, formylphenyl) aniline (65 mL). Was. The resulting mixture was stirred at room temperature for 1 hour and 1N HCl (10 mL)
And washed with 1N HCl (100 mL × 3). The HCl layers were combined, neutralized to pH 12 with 50% NaOH, and extracted with EtOAc (100 mL × 3). The EtOAc layer was dried over Na ₂ S0 _4, concentrated, and purified by column chromatography using (EtOAc hexane) gradient solvent, 2-fluoro-4- (2'-hydroxymethyl phenyl) aniline (3.83 g , 97.6
%). ¹ H NMR (CDCl ₃ ) δ 7.53 (dd, J = 6.6 Hz,
J = 2.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.25 (dd,
J = 6.6 Hz, J = 2.2 Hz, 1H), 7.06 (dd, J = 12.1 Hz)
, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.0 Hz, -J = 1.8 H)
z, 1H), 6.82 (t, J = 8.8 Hz, 1H), 4.63 (s, 2H),
3.79 (bs / 2H); ¹⁹ F NMR (CDCl ₃ ): 5-135.66 (dd, J = 12.21 Hz, J = 9.2 Hz); CIMS (CI) m / z 218 (
M + H, 100%).

To a solution of 2-fluoro-4- (2′-hydroxymethyl-phenyl) aniline (5 g, 23 mmol) in THF (150 mL) was added imidazole (2.35 g,
34.5 mmol) and 2'-tert-butyldimethylsilyl chloride (5.1).
8 g, 34.5 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours.
The mixture was diluted with hexane (150 mL) and washed with water (150 mL). The organic layer was washed with brine, dried over MgSO _4, and purified by column chromatography using hexane and methylene chloride (1t o1), 2-fluoro-4- (
(2′-tert-butyldimethylsilyloxymethyl) phenyl) aniline (
(7.1 g, 92.8%) as a colorless oil. ¹ H NMR (CDCl ₃ )
δ 7.55 (dd, J = 7.7 Hz, J = 1.1 Hz, 1H), 7.35 (d
d, J = 7.4 Hz, J = 1.9 Hz, 1H), 7.30 (dd, J = 9.1 H)
z, J = 1.4 Hz, 1H), 7.20 (dd, J = 7.3 Hz, J = 1.5 H)
z, 1H), 7.05 (dd, J = 12.1 Hz, J = 1.8 Hz, 1H), 6
. 93 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 6.80 (dd, J
= 9.1 Hz, J = 8.0 Hz, 1H), 4.60 (s2H), 3.77 (bs)
, 2H), 0.91 (s, 9H), 0.04 (s, 6H); ¹⁹ F NMR (CD
_{Cl 3): S-136.04;} CIMS: 332 (M + H, 100). Part B: 1- (2-Cyanophenyl) -5-furyl-3-trifluoromethylpyrazole: 4,4,4-Trifluoro-1- (2-) in ethanol (mL)
To a solution of (furyl) -1,3-butanedione (2.06 g, 10 mmol) was added hydrazine monohydrate (0.46 g, 10 mmol). The resulting mixture was refluxed for 16 hours and dried under vacuum to give 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline in almost quantitative yield. ¹ H NMR (CDCl ₃ ) δ 7.
48 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 3.7 Hz, 1H),
6.47 (dd, J = 3.7 Hz, J = 1.9 Hz, 1H), 6.16 (s, 1
H), 3.48 (d, J = 17.9 Hz, 1H), 3.18 (d, J = 17: 9
Hz, 1 H); ¹⁹ F NMR (CDCl ₃ ): S-81.47; ESMS (+): 221 (M + H, 100).

2-Fluorobenzonitrile (0.605 g, 5 mm) in DMF (10 mL)
ol) and 5-furyl-3-trifluoromethyl-3-hydroxy-pyrazoline (1.1 g, to a solution of _{5mmol), CS 2 CO 3 (} 1.63g, 5mmol) was added and the resulting mixture 110 Stirred at C for 16 hours. The mixture was diluted with EtOAc, washed with brine (× 5), dried over MgSO ₄ and purified by column chromatography using a gradient solvent (hexane to ethyl acetate) to give 1- (
2-Cyanophenyl) -5-furyl-3-trifluoromethylpyrazole and 1- (2-cyanophenyl) -3-furyl-5-trifluoromethylpyrazole (1.27 g, 83.8%) were combined with 95 A ratio of 5 was obtained. ¹ H NMR (CDCl ₃ ) δ 7.82 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.77 (
dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.66 (td, J = 7.7)
Hz, J = 1.1 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.
39 (d, J = 1.4 Hz, 1H), 6.96 (s, 1H), 6.37 (dd,
J = 3.3 Hz, J = 1.4 Hz, 1H), 6.04 (d, J = 3.3 Hz, 1
^{H); 19 F NMR (CDCl} 3): 5-62.98; ESMS (+): 304 (M + H, 100).

Part C: 1- (2- (N-Boc-aminomethyl) phenyl) -3-trifluoromethylpyrazol-5-yl-carboxylic acid: 1-(-in DMF (20 mL)
2-cyanophenyl) -5-furyl-3-trifluoromethylpyrazole (1.
To a solution of 5 g, 4.67 mmol) was partially added NaBH ₄ (0.71 g, 18.7 mmol) and then at 0 ° C. COCl ₂ (0.61 g, _4, 67 mmol). After stirring the resulting mixture at room temperature for 18 hours, the black suspension was cooled to 0 ° C. and carefully acidified with 6N HCl (20 mL). The resulting mixture was stirred at room temperature for 3 hours and neutralized to pH 14 with 1N NaOH. Mix the mixture with EtO
Diluted with Ac (100 mL) and filtered through a pad of sand (top) and celite (bottom). The filtrate was separated and the organic layer was washed with brine (5 × 10 mL),
Dried Na ₂ S0 _4, and concentrated to give 1- (2- (aminomethyl) phenyl) -5-furyl-3-trifluoromethyl pyrazole (1.4 g, 91.5%). _{^{1 H NMR (CD 3 OD)}} δ 7.69-7.61 (m, 2H), 7.52 (d, J = 1.5Hz, 1H); 747 (td, J = 7.7Hz, J = 1 .1 Hz,
1H), 7.34 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.
34 (dd, J = 1.8 Hz, J = 3.6 Hz, 1H), 5.75 (d, J = 3
. 3Hz, 1H), 3.40 (s, 2H); ESMS (+): 308 (M + H,
100); To a solution of 1- (2- (aminomethyl) phenyl) -5-furyl-3-trifluoromethylpyrazole (1.4 g, 4.27 mmol) in THF (10 mL) was added THP (10 mL). Of (Boc) ₂ O (1.4 g, 6.4 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was treated with EtOAc (100
mL), washed with water and brine, dried over Na ₂ SO ₄ , concentrated, and crude 1- (2- (N-Boc-aminomethyl) phenyl) -5-furyl-3-triethyl Fluoromethylpyrazole was prepared. ¹ H NMR (CDCl ₃ ) δ 7.60
−7.55 (m, 2H), 7.42 (d, J = 6.2 Hz, 1H), 740 (s
, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.95 (s, 1H), 6
. 28 (dd, J = 1.8 Hz, J = 3.3 Hz, 1H), 5.65 (d, J =
3.3 Hz, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.40 (s,
2H), 1.41 (s, 9H); ¹⁹ F NMR (CDCl ₃ ): δ-62.76.

To a solution of the crude product in acetone (20 mL) and water (20 mL) was partially added KMnO ₄ (3.95 g, 25 mmol) and the resulting mixture was added at 60 ° C. for 20 minutes.
Stirred for minutes and then filtered through celite. The filtrate was concentrated, acidified to pH 4 with 1N HCl and extracted with EtOAc (3 × 50 mL). Wash with organic layer,
Brine, dried over Na ₂ S0 _4, concentrated, and purified by column chromatography using 20% MeOH in dichloromethane, 1- (2- (N-Boc- aminomethyl) phenyl) -3- trifluoroacetic Methyl pyrazol-5-yl-carboxylic acid (
1.05 g, 56% in two steps). ESMS (-): 384.2 (
MH, 100).

Part D: -1- (2- (N-Boc-aminomethyl) phenyl) -3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethylsilyloxymethyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole: CH ₂ Cl ₂ (50mL) solution of 1- (2- (N-Boc- aminomethyl)
(Phenyl) -3-trifluoromethylpyrazol-5-yl-carboxylic acid (0.7
68 g, 2 mmol) in a solution of DMF (1 drop) and oxalyl chloride (0 drop).
. 381 g, 3 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated, and the residue was dissolved in THF (10 mL). To this solution is added THF
2-Fluoro-4- (2 '-(tert-butyldimethylsilyloxymethyl) phenyl) aniline (0.6 g, 1.8 mmol) and E in (10.mL).
t ₃ N was added and (1.5 mL), and the resulting mixture was stirred at room temperature for 24 hours. Dilute the mixture with EtOAc (100 mL), wash with water and brine, add Mg
It was dried over SO ₄ and purified by thin layer chromatography using CH ₂ Cl ₂ / hexane (3: 2) to give 1- (2- (N-Boc-aminomethyl) phenyl) -3-trifluoro Oromethyl-5-[((2-fluoro)-(2′-tert-butyldimethylsilyloxymethyl)-(1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole (0.49 g, 80% ) Got.

1- (2′-N-Boc-aminomethylphenyl)-in THF (10 mL)
3-Trifluoromethyl-5-[((2-fluoro)-(2′-tert-butyldimethylsilyloxymethyl]-[1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole (0. BU ₄ NF (1M in THF, 3 mL) was added to a solution of 57 g, 0.93 mmol) and the resulting solution was stirred at room temperature for 2 hours The mixture was diluted with EtOAc (150 mL) and washed with water (20 mL) , dried over Na ₂ S0 _4, and purified by column chromatography using (EtOAc hexane) gradient solvent .1- (2- (N-Boc- aminomethyl) phenyl) -3-trifluoromethyl - 5-[((2-Fluoro)-(2′-hydroxymethyl)-[1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole (484 mg, −10 ¹ H NMR (CD ₃ OD) δ 7.69
(T, J = 8.0 Hz, 1H), 7.55-7.27 (m, 9H), 7.21 (
dd, J = 7.4 Hz, J = 1.8 Hz, 1H), 7.13 (dd, J = 8.4)
Hz, J = 1.1 Hz, 1H), 4.46 (s, 2H), 4.05 (s, 2H)
, 1.34 (s, 9H); 19 F NMR (CD 3 OD): δ-64.08, -1 25.53; ESMS (+): 606.3 (M + Na, 100).

Part E: 1- (2- (aminomethyl) phenyl) -3-trifluoromethyl-5-[((2-fluoro)-(2′-pyrrolidinomethyl)-[1,1 ′] -Biphen-4-yl) aminocarbonyl] pyrazole, TFA salt: THF (5 mL
1)-(2- (N-Boc-aminomethyl) phenyl) -3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethyl)-[1,1 ′)
] -Bifen-4-yl) aminocarbonyl] pyrazole (150 mg, 0.2
6 mmol) in a solution of CS ₂ CO ₃ (167 mg, 0.51 mmol) and Ms
CI (4 mg, 0.39 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, then concentrated, the residue was dissolved in THF (10 mL) and treated with pyrrolidine (0.5 mL) at room temperature for 8 hours. ESMS (+): 638.4 (M + H, 100
). This mixture was treated with TFA.CH ₂ Cl ₂ (1 to 1, 10 mL) at room temperature for 5 hours and concentrated. The residue was purified with a gradient solvent (H ₂ O—CH ₃ CN—0.05% T
Purification by HPLC on C18 using FA) afforded the title compound (50 mg, 3 mg).
6% in two steps). ¹ H NMR (CD ₃ OD) δ 7.80 (T, J = 8.
1HZ, 1H), 7.71-7.30 (m, 9H), 7.27 (dd, J = 11
. 3 Hz, J = 1.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H),
4.40 (s, 2H), 3.99 (s, 2H), 3.42-3.34 (m, 2H)
), 2.93-2.87 (m, 2H) , 2.00-1.94 (m, 4H); 19 F
_{NMR (CD 3 OD): 5-64.22} , -77.57 (TFA), - 123. _{82; HRMS: C 29 H 28} O 1 F 4 N 5 to 538.2243.

Example 46 1- [2- (Aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2′-hydroxymethyl)-[1,1 ′]-biphen-4
-Yl) aminocarbonyl] pyrazole / TFA 1- (2- (N-Boc-aminomethyl) phenyl) -3-trifluoromethyl-5-[((2-fluoro)-(2'-hydroxymethylsilyloxy Methyl)-[1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole (10
mg) solution with TFA / CH ₂ Cl ₂ (1: 1, 1 mL) at room temperature for 3 hours,
Concentrated. The residue was purified by HPLC on C18 using a gradient solvent _{(H 2 O-CH 3 CN} -0.05% TFA), to give the title compound (2 mg). _{^{1 H NMR (CD 3 OD)}} : δ 7.66-7.45 (m, 6H), 7.38-7. 21 (m, 4H), 7.15 (d, J = 9.5 Hz, 1H), 7, 10 (d,
J = 6.6 Hz, 1H), 4.39 (s, 2H), 3.91 (s, 2H); ¹⁹ F
_{NMR (CD 3 OD): δ} -64.23, -77.38, -125.40; E SMS (-): 483.2 (M-H, 100).

Table 1

[0275]

Embedded image

[0276]

[Table 1-1]

[Table 1-2]

The following table contains representative examples of the present invention. Each entry in each table is meant to be paired with the first respective expression in the table. For example, Example 1 in Table 2 shows that each expression a
-Bbbb means to be paired. Example 1 in Table 3 shows that each of the formulas a-bbb
b means a pair.

The following groups are meant for groups A in the table.

[0279]

Embedded image

Table 2

[0281]

Embedded image

[0282]

Embedded image

[0283]

Embedded image

[0284]

Embedded image

[0285]

Embedded image

[0286]

[Table 2-1]

[0287]

[Table 2-2]

[0288]

[Table 2-3]

[0289]

[Table 2-4]

[0290]

[Table 2-5]

[0291]

[Table 2-6]

[0292]

[Table 2-7]

[0293]

[Table 2-8]

[0294]

[Table 2-9]

[0295]

[Table 2-10]

[0296]

[Table 2-11]

[0297]

[Table 2-12]

[0298]

[Table 2-13]

[0299]

[Table 2-14]

[0300]

[Table 2-15]

[0301]

[Table 2-16]

[0302]

[Table 2-17]

[0303]

[Table 2-18]

[0304]

[Table 2-19]

[0305]

[Table 2-20]

[0306]

[Table 2-21]

[0307]

[Table 2-22]

Table 3

[0309]

Embedded image

[0310]

Embedded image

[0311]

Embedded image

[0312]

Embedded image

[0313]

Embedded image

[0314]

[Table 1-1]

[0315]

[Table 2-2]

Table 4

[0317]

Embedded image

[0318]

Embedded image

[0319]

Embedded image

[0320]

Embedded image

[0321]

[Table 3-1]

[0322]

[Table 4-2]

[0323]

[Table 5-3]

[0324]

[Table 6-4]

[0325]

[Table 7-5]

[0326]

[Table 8-6]

[0327]

[Table 9-7]

[0328]

[Table 10-8]

[0329]

[Table 11-9]

[0330]

[Table 12-10]

[0331]

[Table 13-11]

[0332]

[Table 14-12]

[0333]

[Table 15-13]

[0334]

[Table 16-14]

[0335]

[Table 17-15]

[0336]

[Table 18-16]

[0337]

[Table 19-17]

[0338]

[Table 20-18]

[0339]

[Table 21-19]

[0340]

[Table 22-20]

[0341]

[Table 23-21]

[0342]

[Table 24-22]

Table 5

[0344]

Embedded image

[0345]

Embedded image

[0346]

Embedded image

[0347]

Embedded image

[0348]

[Table 25-1]

[0349]

[Table 26-2]

(Utility) The compound of the present invention is useful as an anticoagulant for treating or preventing thromboembolic disease in mammals. The term "thromboembolic disorder" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, e.g., unstable angina, primary or recurrent myocardial infarction, ischemic Sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral artery thrombosis, cerebral embolism, renal embolism, Including pulmonary embolism. The anticoagulant effect of the compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of the compound of the present invention as a factor Xa inhibitor was evaluated using purified human factor Xa and a synthetic substrate. Chromogenic substrate S2222 (Kabi Pharma)
(Xia, Franklin, Ohio) Factor Xa hydrolysis rates were measured both in the presence and absence of the compounds of the present invention. Hydrolysis of this substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nm. A decrease in the rate of change of the absorbance at 405 nm in the presence of the inhibitor indicates inhibition of the enzyme. The results of this assay are expressed as inhibition constants Ki.

[0352] 0.10M containing 0.20M NaCl and 0.5% PEG 8000
Factor Xa was measured in a sodium phosphate buffer (pH 7.5). The Michaelis constant, Km, for the hydrolysis of the substrate was determined using the Lineweaver-Burk method as 2
Determined at 5 ° C. Ki values range from 0.2 to 0.5 nM of human factor Xa (Enzyme).
Research Laboratories, South Bent, IN) was determined by reacting with a substrate (0.20 mM to 1 mM) in the presence of an inhibitor. The reaction was continued for 30 minutes and the rate (rate of change in absorbance over time) was 2
Measurements were taken on a time frame of 5 to 30 minutes. The Ki value was calculated using the following relational expression.

(Vo−vs) / vs = I / (Ki (1 + S / Km)) where vo is the rate of control in the absence of inhibitor and vs is the rate in the presence of inhibitor I is the concentration of the inhibitor; Ki is the dissociation constant of the enzyme-inhibitor complex; S is the concentration of the substrate; Km is the Michaelis constant.

Using the above methodology, many of the compounds of the present invention were found to exhibit Ki ≦ 10 μM, confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of the compounds of the present invention can be shown in a rabbit arteriovenous (AV) shunt thrombosis model. In this model, xylazine (10 mg / kg im.
) And ketamine (50 mg / kg im) weighed 2-3
kg rabbits were used. A saline-filled AV shunt device was connected between the femoral artery and the femoral vein cannula. The AV shunt device consists of a 6 cm tygon tube containing silk thread. Blood flows from the femoral artery via the AV shunt to the femoral vein. Exposure of the blood stream to silk induces significant thrombus formation. 4
After 0 minutes, remove the shunt and weigh the silk thread covered with the thrombus. The test agent or vehicle is given before opening the AV shunt (iv, ip, sc).
Or oral). The percent inhibition of thrombus formation for each treatment group is determined. ID50 value (
The dose that inhibits thrombus formation by 50%) is determined by linear regression.

The compounds of formula (I) may also be useful as inhibitors of serine prostheses, especially human thrombin, plasma kallikrein and plasmin. These compounds, due to their inhibitory action, are physiologically catalyzed by enzymes of the aforementioned kind,
Suggested for use in the prevention or treatment of coagulation and inflammation. In particular, the compounds are useful as agents for the treatment of diseases caused by elevated thrombin activity, such as myocardial infarction, and as anticoagulants in the processing of blood into plasma for diagnostic and other commercial purposes. It has utility as a reagent to be used.

Some of the compounds of the present invention have been shown to be direct inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purification system. Kettner et al., J. Am. Biol. Chem. 265, 18289-18297, 19
In vitro inhibition constants were determined by the method described in 1990. In such an assay, the chromogenic substrate S 2238 (Helena Labora)
(Triees, Beaumont, TX) was monitored spectrophotometrically for thrombin-mediated hydrolysis. Addition of the inhibitor to the assay mixture reduces the absorbance, indicating inhibition of thrombin. Human thrombin (Enzyme Research Labora) at a concentration of 0.2 nM in a 0.10 M sodium phosphate buffer (pH 7.5, 0.20 M NaCl, 0.5% PEG 6000).
tories, Inc. (South Bend, IN) was incubated with various substrate concentrations from 0.20 to 0.02 mM. After a 25 to 30 minute incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm resulting from hydrolysis of the substrate. Inhibition constants as a function of substrate concentration were derived from reciprocal plots of reaction rates using the standard Lineweaver-Burk method. Evaluation of some compounds of the invention using the methods described above revealed a Ki of less than 10 μm, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents. These include other anticoagulants or anticoagulants, antiplatelet or platelet inhibitors, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

A therapeutically effective amount of the present compounds is administered to a mammal. "Therapeutically effective amount" refers to a compound of Formula I, alone or in combination with another therapeutic agent, for preventing or ameliorating a thromboembolic disease state or progression. Mean effective amount of the compound.

“Administered in combination” or “combination therapy” means that the compound of Formula I and one or more other therapeutic agents are administered to the mammal to be treated at the same time. When administered in combination, each component may be administered simultaneously or sequentially in any order at different times. Thus, each component may be administered separately, but sufficiently close in time to achieve the desired therapeutic effect.
Other anticoagulants (or anticoagulants) that can be used in combination with the compound of the present invention
Include warfarin and heparin, in addition to other factor Xa inhibitors as described in the publications described above in the Background of the Invention.

The term antiplatelet agent (or platelet inhibitor) as used herein refers to an agent that inhibits platelet function, such as inhibiting platelet aggregation, adhesion, or granule secretion. Such drugs include aspirin, ibuprofen, naproxen,
Including various known non-steroidal anti-inflammatory drugs (NSAIDS) such as sulindac, indomethacin, mefenamic acid, droxicam, diclofenac, sulfinpyrazone, and piroxicam, and pharmaceutically acceptable salts or prodrugs thereof However, it is not limited to these. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Other suitable antiplatelet agents include ticlopidine and its pharmaceutically acceptable salts or prodrugs. Ticlopidine is a preferred compound because it is known to be gentle on the gastrointestinal tract during use. Yet other suitable platelet inhibitors include II
b / IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthase inhibitors, and pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitor (or antithrombin agent) as used herein refers to an inhibitor of the serine protease thrombin. By inhibiting thrombin, thrombin-mediated platelet activation (ie, eg, platelet aggregation,
And / or granule secretion of plasminogen activator inhibitor-1 and / or serotonin) and / or fibrin formation. Many thrombin inhibitors are known to those of skill in the art and these inhibitors are contemplated for use in combination with the compounds of the present invention. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparin, hirudin, and argatroban, and pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides are
The N of boronic acids such as lysine, ornithine, arginine, homoarginine and their corresponding isothiouronium analog C-terminal α-aminoboronic acid derivatives
-Including acetyl and peptide derivatives. The term hirudin as used herein includes suitable derivatives or analogs of hirudin, such as disulfatohirudin, and is referred to herein as hirulog. Boropeptide thrombin inhibitors include the compounds described in Kettner et al., US Pat. No. 5,187,157 and EP-A-293 881 A2, the disclosure of which is incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication No. 92/07869 and European Patent Application Publication No. 471,651 A2, the disclosure of which is hereby incorporated by reference. Include in the specification. .

As used herein, the term thrombolytic (or fibrinolytic) agent (or thrombolytic or fibrinolytic) means an agent that lyses blood clots (thrombus). Such drugs include tissue plasminogen activator, anistreplase (
anistreplace), urokinase, or streptokinase, and pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase as used herein is described, for example, in European Patent Application 028
No., 489, the disclosure of which is incorporated herein by reference.
Anisoylated plasminogen streptokinase activator complex. As used herein, the term urokinase is
It is intended to mean both double-stranded and single-stranded urokinase, the latter also being referred to herein as pro-urokinase.

The co-administration of a compound of the formula I according to the invention with such another therapeutic agent can be more potent than the compound and the therapeutic agent alone, achieving this with the use of lower doses of each. Can be. Lower doses minimize the potential for side effects, which can increase the safety margin.

The compounds of the present invention are also useful as standards or reference compounds, eg, as quality standards or controls, in tests or assays involving the inhibition of factor Xa. Such compounds can be provided in commercially available kits, for example, Xa
It may be provided for use in pharmaceutical research related to factors. For example, a compound of the present invention can be used in an assay as a reference to compare its known activity to a compound of unknown activity. This assures the experimenter that the analysis has been performed accurately and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new analytical methods or protocols, the compounds according to the invention can be used to test their effectiveness.

The compounds of the invention can also be used in factor Xa related diagnostic assays. For example, the presence of Factor Xa in an unknown sample can be determined by adding the chromogenic substrate S2222 to a test sample and optionally to a series of solutions containing one of the compounds of the invention.
Can be evaluated. If the production of pNA is observed in a solution containing the test sample but without the compound of the invention, the presence of factor Xa can be concluded.

(Dose and Formulation) The compound of the present invention can be prepared in the form of tablets, capsules (each containing a sustained release formulation or sustained release formulation), pills, powders, granules, elixirs, tinctures, suspensions , Syrups, and emulsions can be administered as oral dosage forms. These are intravenous (
(Bolus or infusion), intraperitoneal, subcutaneous, or intramuscular injection, all using dosage forms well known to those skilled in the pharmaceutical arts. These can be administered alone, but are generally administered with a pharmaceutical carrier chosen based on the chosen route of administration and standard pharmaceutical practice.

The regimen of administration of the compounds of the invention will, of course, include the pharmacodynamic properties of the individual drugs and their types and routes of administration; the species, age, sex, health, medical condition and weight of the recipient; Degree depends on known factors such as type of combination therapy; number of treatments; route of administration, renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the thromboembolic disease.

As a general guide, a daily oral dose of each active ingredient, when used for the indicated effect, is between about 0.001 and 1000 mg / kg of body weight, preferably about 0,1 mg / kg of body weight per day. It ranges between 01 and 100 mg / kg of body weight, and most preferably between about 1.0 and 20 mg / kg / day. Intravenously, the most preferred dose is
During a constant rate infusion, it ranges from about 1 to about 10 mg / kg / min. The compounds of the present invention can be administered in a single daily dose or in a total daily dose of two, three or four times daily.

The compounds of the present invention can be administered in nasal form, by topical use of a suitable nasal vehicle, or by the transdermal route, using dermal patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be
It is continuous rather than intermittent.

The compounds may be suitably selected for the intended dosage form, ie, oral tablets, capsules, elixirs, syrups, and the like, and appropriate pharmaceutical diluents, consistent with conventional pharmaceutical practice, It is usually administered in admixture with an excipient, or carrier (herein generically referred to as a pharmaceutical carrier).

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient can be lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Or non-toxic orally, pharmaceutically acceptable inert carriers. For oral administration in liquid form, the oral pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia or tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. It is. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

The compounds of the present invention can also be combined with soluble polymers as targetable pharmaceutical carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-
It can include phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Further, the compound of the present invention may contain a biodegradable polymer (for example, polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid) useful for achieving controlled release of a drug. Block copolymers of polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphiphilic hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration are from about 1 milligram to about 1 milligram per dosage unit.
It can contain 00 milligrams of active ingredient. In these pharmaceutical compositions,
The active ingredient is usually present in an amount of about 0.5-95% by weight, based on the total weight of the composition.

Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Compressed tablets can be made with similar diluents. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask unpleasant taste and protect the tablets from the atmosphere, or can be enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

Generally, water, suitable oils, saline, aqueous dextrose (glucose), related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering agents. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Mack, a standard reference book in the art.
It is described in “Remington's Pharmaceutical Sciences” by the Publishing Company.

Representative pharmaceutical forms effective for administering the compounds of the present invention can be shown as follows.

Capsules Many unit capsules contain standard two-piece hard gelatin capsules each.
It can be prepared by charging 100 milligrams of the powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

Soft Gelatin Capsules A mixture of the active ingredients is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil and injected into the gelatin by a positive displacement pump to form a soft gelatin containing 100 milligrams of the active ingredient. Capsules can be formed. The capsule is washed and dried.

Tablets Tablets can be prepared by conventional methods, the dosage unit being 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystals Cellulose, 11 milligrams starch and 98.8 milligrams lactose. Appropriate coatings can be applied to increase palatability or delay absorption.

Injectables Parenteral compositions suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume aqueous propylene glycol. The solution is made isotonic with sodium chloride and sterilized.

Suspensions Aqueous suspensions can be prepared for oral administration, each containing 100 mg in 5 mL.
, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP) and 0.025 mL of vanillin.

When the compound of the present invention is administered in combination with other anticoagulants, for example, the daily dose may be about 0.1 to 100 milligrams of the compound of formula I per kilogram of patient body weight and another The anticoagulant can be about 1 to 7.5 milligrams. For tablet dosage forms, the compound of the invention will usually be present in an amount of about 5 to 10 milligrams per dosage unit, and another anticoagulant in an amount of about 1 to 5 milligrams per dosage unit. .

When a compound of formula I is administered in combination with an antiplatelet agent according to the general guidelines, typically the daily dose will be from about 0.01 to about 0.01 to about 0.01 kg of compound per kilogram of patient body weight. 25 milligrams and about 50 to 150 milligrams of the antiplatelet agent, preferably about 0.1 to 1 milligram of the compound of formula I and about 1 to 3 milligrams of the antiplatelet agent.

When a compound of formula I is used in combination with a thrombolytic agent, typically the daily dose can be from about 0.1 to 1 milligram of compound of formula I per kilogram of patient body weight. , And in the case of thrombolytics, the usual dose when the thrombolytic is administered alone can be reduced by about 70-80% when administered with a compound of formula I.

When two or more of the other aforementioned therapeutic agents are administered in combination with a compound of Formula I,
In general, the typical daily dose and the amount of each component in a typical dosage form will vary depending on the additive or synergistic effect of the therapeutic agent when co-administered. It can be reduced compared to the usual dose.

[0390] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when a compound of Formula I and another therapeutic agent are combined in a single dosage unit, physical contact between the active ingredients is minimized even if the active ingredients are combined in a single dosage unit. These are formulated to be (ie, reduced). For example, one active ingredient may be enteric coated. Enteric coating of one of the active ingredients not only minimizes contact between the combined active ingredients, but also one of these ingredients is released in the intestine instead of in the stomach As such, the release of one of these components in the gastrointestinal tract can be controlled. One of the active ingredients can also be coated with a substance that has a sustained release effect throughout the gastrointestinal tract and that serves to minimize contact between the active ingredients used in combination. In addition, sustained release components can be further enteric coated so that release of the component occurs only in the intestine. To further separate the active ingredients, one ingredient may be coated with a sustained release and / or enteric polymer and the other ingredient may be a polymer such as low viscosity grade hydroxypropylmethylcellulose (HPMC) or known in the art. Still other methods of coating with other suitable materials are used to formulate combination products. The polymer coating serves as an additional barrier to interaction with other components.

These and other methods of minimizing contact between the combination product components of the invention can be administered in a single dosage form or in separate dosage forms but at the same time and contemporaneously. Whether or not they will be readily apparent to those of skill in the art once understood of the present disclosure.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that, within the scope of the following claims, they may be practiced otherwise than as specifically described herein.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4439 A61K 31/4439 31/454 31/454 A61P 7/02 A61P 7/02 C07D 231/22 C07D 231/22 B 231/24 231/24 249/04 506 249/04 506 257/04 257/04 D 401/12 401/12 401/14 401/14 403/12 403/12 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AU, BR, CA, CN, CZ, EE, HU, IL, JP, KR, LT, LV, MX, NO, NZ, PL, RO, SG, SI, SK, UA, VN (72) Inventor Bost Beam Lori El. United States 19711 Newark Linn Hall 6 Delaware 6 (72) Inventor Rossi Karen Anita United States 19711 Newark Emery Court 120A F Term (Del.) 4C063 AA01 AA03 BB09 CC22 CC25 CC29 CC47 CC54 DD03 DD10 DD12 DD22 EE01 4C086 AA01 AA03 BC07 BC17 BC21 BC36 BC38 BC42 BC60 BC62 BC73 GA09 MA01 MA04 MA22 MA23 MA35 MA37 MA41 MA66 NA14 ZA54

Claims (22)

[Claims] 1. A compound of formula I:Or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring M contains 0-3 N atoms in addition to J, provided that M is 2 N atom
When containing^1bIs absent and if M contains three N atoms, R^1a And R^1bIs absent; J is N or NH; D is CN, C (= NR⁸) NR⁷R⁹, NHC (= NR⁸) NR⁷R⁹, NR⁸CH (= NR⁷), C (O) NR⁷R⁸, And (CR⁸R⁹)_tNR⁷R⁸Selected from
With the proviso that D is substituted ortho to G on E; E is phenyl, pyridyl, pyrimidyl, pyrazinyl substituted with 1-2 R
R is H, Cl, F, Br, I, (CH_Two)_tOR^Three, C_{1 ~ Four}Alkyl, OCF_Three , CF_Three, C (O) NR⁷R⁸, And (CR⁸R⁹)_tNR⁷R⁸G is absent or NHCH_Two, OCH_Two, And SCH_TwoWherein s is 0, G is attached to a carbon atom on ring M; Z is C_{1 ~ Four}Alkylene, (CH_Two)_rO (CH_Two)_r, (CH_Two)_rNR^Three(CH_Two )_r, (CH_Two)_rC (O) (CH_Two)_r, (CH_Two)_rC (O) O (CH_Two)_r, (CH_Two)_rOC (O) (CH_Two)_r, (CH_Two)_rC (O) NR^Three(CH_Two)_r, (CH_Two) _r NR^ThreeC (O) (CH_Two)_r, (CH_Two)_rOC (O) O (CH_Two)_r, (CH_Two)_rO
C (O) NR^Three(CH_Two)_r, (CH_Two)_rNR^ThreeC (O) O (CH_Two)_r, (CH_Two)_r NR^ThreeC (O) NR^Three(CH_Two)_r, (CH_Two)_rS (O)_p(CH_Two)_r, (CH_Two)_r SO_TwoNR^Three(CH_Two)_r, (CH_Two)_rNR^ThreeSO_Two(CH_Two)_r, And (CH_Two)_rN
R^ThreeSO_TwoNR^Three(CH_Two)_rWherein Z is a ring M or a group A and N—N, N—O, N—S, NCH_TwoN, NCH_TwoO or NCH_TwoDoes not form an S bond; R^1aAnd R^1bAre independently absent or-(CH_Two)_r-R^{1 '}, -CH = CH-R^{1 '}, NCH_TwoR^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, NH (CH_Two)_Two (CH_Two)_tR^{1 '}, O (CH_Two)_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two )_tR^{1 '}Or R^1aAnd R^1bAre bonded to adjacent carbon atoms when they are
Together with the joining atoms, from 0 to 2 R^Four5-8 membered saturated, containing 0-2 heteroatoms selected from the group consisting of N, O, and S 1,
Forming a partially saturated or unsaturated ring;^{1 '}Is H, C_{1 ~ Three}Alkyl, F, Cl, Br, I, -CN, -CHO, (CF_Two)_rCF_Three, (CH_Two)_rOR^Two, NR^TwoR^2a, C (O) R^2c, OC (O) R^Two,
(CF_Two)_rCO_TwoR^2c, S (O)_pR^2b, NR^Two(CH_Two)_rOR^Two, CH (= NR^2c ) NR^TwoR^2a, NR^TwoC (O) R^2b, NR^TwoC (O) NHR^2b, NR^TwoC (O)_TwoR^{Two a} , OC (O) NR^2aR^2b, C (O) NR^TwoR^2a, C (O) NR^Two(CH_Two)_rOR^Two , SO_TwoNR^TwoR^2a, NR^TwoSO_TwoR^2b, 0-2 R^FourC substituted with_{Three ~ 6}A carboxylic acid residue and 1 to 4 hetero atoms selected from the group consisting of N, O and S
Containing 0 to 2 R^FourR is selected from a 5- to 10-membered heterocyclic ring system substituted with^{1 "}Is H, CH (CH_TwoOR^Two)_Two, C (O) R^2c, C (O) NR^TwoR^2a, S (O) R^2b, S (O)_TwoR^2bAnd SO_TwoNR^TwoR^2aSelected from; R^TwoIs, in each case, H, CF_Three, C_{1 ~ 6}Alkyl, benzyl, 0-2 R ^4b C substituted with_{Three ~ 6}From the group consisting of carboxylic acid residues and N, O and S
0 to 2 R containing 1 to 4 heteroatoms selected^4bReplaced with 5
R is selected from a 6-membered heterocyclic ring system; R^2aIs, in each case, H, CF_Three, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}A group consisting of carboxylic acid residues and N, O and S
0 to 2 R containing 1 to 4 heteroatoms selected from^4bReplaced by
R is selected from a 5- to 6-membered heterocyclic ring system; R^2bIs, in each case, CF_Three, C_{1 ~ Four}Alkoxy, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}Carboxylic acid residues, and N, O, and
0 to 2 R containing 1 to 4 heteroatoms selected from the group consisting of S^4b R is selected from a 5-6 membered heterocyclic ring substituted with^2cIs, in each case, CF_Three, OH, C_{1 ~ Four}Alkoxy, C_{1 ~ 6}Alkyl, benzyl, 0-2 R^4bC substituted with_{Three ~ 6}Carboxylic acid residues, and N, O,
0 to 2 containing 1 to 4 heteroatoms selected from the group consisting of
R^4bR is selected from a 5-6 membered heterocyclic ring system;^TwoAnd R^2aIs bonded to and contains 0 to 1 heteroatoms containing 0 to 1 heteroatoms selected from the group consisting of N, O, and S;^4bReplaced by 5 or
Selected from 6 membered saturated, partially saturated or unsaturated rings;^TwoAnd R^2aContains 0 to 1 heteroatoms selected from the group consisting of N, O, and S, which are bonded together with the atoms to which they are bonded.
0 to 2 R^4b5 or 6 membered saturated, partially saturated or unsaturated,
Forming a saturated ring; R^ThreeIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3aIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3bIs, in each case, H, C_{1 ~ Four}Selected from alkyl, and phenyl; R^3cIs in each case C_{1 ~ Four}A is 0 to 2 R^FourC substituted with_{Three ~ Ten}Carboxylic acid residues and N, O, and
And 2 containing from 1 to 4 heteroatoms selected from the group consisting of
R^FourB is XY, NR selected from a 5-10 membered heterocyclic ring substituted with^TwoR^2a, C (= NR^Two) NR^TwoR^2a, NR^TwoC (= NR^Two) NR^TwoR^2a, 0-2 R^4aC substituted with_{Three ~ Ten}Carboxylic acid residues and N, O
And 0 to 2 containing 1 to 4 heteroatoms selected from the group consisting of
R^4aX is selected from the group consisting of a 5-10 membered heterocyclic ring substituted with_{1 ~ Four}Alkylene, -CR^Two(CR^TwoR^2b) (CH_Two)_t-, -C (O)-
, -C (= NR^{1 "})-, -CR^Two(NR^{1 "}R^Two)-, -CR^Two(OR^Two)-, -C
R^Two(SR^Two)-, -C (O) CR^TwoR^2a-, -CR^TwoR^2aC (O), -S (O)_p -, -S (O)_pCR^TwoR^2a-, -CR^TwoR^2aS (O)_p-, -S (O)_TwoNR^Two−,
-NR^TwoS (O)_Two-, -NR^TwoS (O)_TwoCR^TwoR^2a-, -CR^TwoR^2aS (O)_TwoNR^Two, -NR^TwoS (O)_TwoNR^Two-, -C (O) NR^Two-, -NR^TwoC (O)-, -C
(O) NR^TwoCR^TwoR^2a-, -NR^TwoC (O) CR^TwoR^2a-, -CR^2aR^2aC (O)
NR^Two-, -CR^TwoR^2aNR^TwoC (O)-, -NR^TwoC (O) O-, -OC (O) N
R^Two-, -NR^TwoC (O) NR^Two-, -NR^Two-, -NR^TwoCR^TwoR^2a-, -CR^TwoR^{Two a} NR^Two-, O, -CR^TwoR^2aO- and -OCR^TwoR^2aY is selected from (CH_Two)_rNR^TwoR^2a(However, XY does not form NN, ON, or SN bonds), 0 to 2 R^4aC substituted with_{Three ~ Ten}Containing a carboxylic acid residue and 1-4 heteroatoms selected from the group consisting of N, O, and S
0 to 2 R^4aR is selected from a 5-10 membered heterocyclic ring substituted with^FourIs, in each case, H, ＯO, (CH_Two)_rOR^Two, F, Cl, Br, I, C _{1 ~ Four} Alkyl, -CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2c , NR^TwoC (O) R^2b, C (O) NR^TwoR^2a, NR^TwoC (O) NR^TwoR^2a, CH (=
NR^Two) NR^TwoR^2a, CH (= NS (O)_TwoR^Five) NR^TwoR^2a, NHC (= NR^Two) N
R^TwoR^2a, C (O) NHC (= NR^Two) NR^TwoR^2a, SO_TwoNR^TwoR^2a, NR^TwoSO_Two NR^TwoR^2a, NR^TwoSO_Two-C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, (C
F_Two)_rCF_Three, NCH_TwoR^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, N (CH_Two)_Two(CH_Two)_tR^{1 '}, O (CH_Two)_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two)_tR ^{1 '} Or one R^FourR is selected from a 5- to 6-membered aromatic heterocyclic group containing 1-4 heteroatoms selected from the group consisting of N, O, and S;^4aIs, in each case, H, ＯO, (CH_Two)_rOR^Two, (CH_Two)_r-F, (CH_Two)_r-Br, (CH_Two)_r-Cl, Cl, Br, F, I, C_{1 ~ Four}Alkyl, -C
N, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2c, NR^TwoC (O) R^{Two b} , C (O) NR^TwoR^2a, C (O) NH (CH_Two)_TwoNR^TwoR^2a, NR^TwoC (O) NR ^Two R^2a, CH (= NR^Two) NR^TwoR^2a, NHC (= NR^Two) NR^TwoR^2a, SO_TwoNR^Two R^2a, NR^TwoSO_TwoNR^TwoR^2a, NR^TwoSO_Two-C_{1 ~ Four}Alkyl, C (O) NHSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^FiveAnd (CF_Two)_rCF_ThreeChoose from
Or one R^4aRepresents 1-4 selected from the group consisting of N, O, and S
0 to 1 R containing two heteroatoms^FiveR is selected from a 5- to 6-membered aromatic heterocyclic group substituted with^4bIs, in each case, H, ＯO, (CH_Two)_rOR^Three, F, Cl, Br, I, C_{1 ~ Four}Alkyl, -CN, NO_Two, (CH_Two)_rNR^ThreeR^3a, (CH_Two)_rC (O) R ^Three , (CH_Two)_rC (O) R^3c, NR^ThreeC (O) R^3a, C (O) NR^ThreeR^3a, NR^ThreeC
(O) NR^ThreeR^3a, CH (= NR^Three) NR^ThreeR^3a, NR^ThreeC (= NR^Three) NR^ThreeR^3a,
SO_TwoNR^ThreeR^3a, NR^ThreeSO_TwoNR^ThreeR^3a, NR^ThreeSO_Two-C_{1 ~ Four}Alkyl, NR^ThreeS
O_TwoCF_Three, NR^ThreeSO_Two-Phenyl, S (O)_pCF_Three, S (O)_p-C_{1 ~ Four}Alkyl, S (O)_p-Phenyl, and (CF_Two)_rCF_ThreeSelected from; R^FiveIs, in each case, CF_Three, C_{1 ~ 6}Alkyl, 0-2 R⁶And 0 to 2 R⁶R selected from benzyl substituted with⁶Is, in each case, H, OH, (CH_Two)_rOR^Two, Halo, C_{1 ~ Four}Alkyl,
CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, NR^TwoC (O) NR^TwoR^2a, CH (= NH) NH_Two, NHC (= NH) NH_Two , SO_TwoNR^TwoR^2a, NR^TwoSO_TwoNR^TwoR^2a, And NR^TwoSO_TwoC_{1 ~ Four}Selected from alkyl; R⁷Is in each case H, OH, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl carbonyl, C_{1 ~ 6}Alkoxy, C_{1 ~ Four}Alkoxycarbonyl, (CH_Two)_n-Phenyl,
C_{6 ~ Ten}Aryloxy, C_{6 ~ Ten}Aryloxycarbonyl, C_{6 ~ Ten}Aryl methylcarbonyl, C_{1 ~ Four}Alkylcarbonyloxy C_{1 ~ Four}Alkoxycarboni
Le, C_{6 ~ Ten}Arylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{1 ~ 6}Alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C_{1 ~ Four}A
Selected from alkoxycarbonyl; R⁸Is, in each case, H, C_{1 ~ 6}Alkyl and (CH_Two)_n-Phenyl; or R⁷And R⁸Combine to form a member selected from the group consisting of N, O, and S
Form a 5 or 6 membered saturated ring containing 0 to 1 additional heteroatoms
R⁹Is, in each case, H, C_{1 ~ 6}Alkyl and (CH_Two)_nN is in each case selected from 0, 1, and 3; m is in each case selected from 0, 1, and 2 p is in each case selected from 0, 1, and 2 R is selected from 0, 1, 2, and 3 in each case; s is selected from 0, 1, and 2 in each case; t Is in each case selected from 0, 1, 2, and 3; provided that D-E-G- (CH_Two)_s-And -ZAB are both benzamido.
A compound which is not gin. 2. The compound according to claim 1, wherein the compound has the formula Ia-I
h; Wherein the groups D-E- and -Z-A-B are attached to adjacent atoms on the ring; R is, H, Cl, F, Br , I, (CH 2) t OR 3, C _1-4 is selected from alkyl, _{OCF 3, CF 3, C (} O) NR 7 R 8 _{^{and, (CR 8 R 9) t}} NR 7 R 8; Z _{is, CH 2 O, OCH 2,} CH 2 NH, NHCH ₂ , C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (
CH ₂ ), SO ₂ NH and NHSO ₂ , wherein Z does not form an N—N, N—O, NCH ₂ N, or NCH ₂ O bond with ring M or group A; of 0-2 is substituted with R ⁴ carbocyclic and heterocyclic ring systems; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl , Imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4
-Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,2
5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl B is selected from the group consisting of Y, XY, NR ² R ^2a , C ( = NR ² ) NR ² R ^2a and NR ² C (=
NR ²⁾ is selected from NR ² R ^2a; X is, C _{1 ~ 4} alkylene, -C (O) -, - C (= NR) -, - CR 2 (NR 2 R 2a) -, - C (O ^{) CR 2 R 2a -, -} CR 2 R 2a C (O), - C (O) NR 2 -, -NR 2 C (O) -, - C (O) NR 2 CR 2 R 2a -, - NR ^{2 C (O) CR 2 R} 2 a -, - CR 2 R 2a C (O) NR 2 -, - CR 2 R 2a NR 2 C (O) -, - NR 2 C (
^{O) NR 2 -, - NR} 2 -, - NR 2 CR 2 R 2a -, - CR 2 R 2a NR 2 -, O, -C
R is selected from R ² R ^2a O— and —OCR ² R ^2a —; Y is NR ² R ^2a , provided that XY does not form an NN or ON bond; A carbocyclic and heterocyclic ring system substituted with 0 to 2 R ^4a ; cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, Oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,
2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-
Selected from one of triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzoisothiazolyl, and isoindazolyl; K is selected from O, S, NH and N; A compound comprising: 3. The compound according to claim 2, wherein said compound is of the formula IIa-II
Represented by f: In the formula, Z is C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (
O) NH, C (O) N (CH ₃ ), CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH, and NHSO ₂ , wherein Z is a ring M or A compound which does not form an NN or NCH ₂ N bond with the group A. 4. The compound according to claim 3, wherein E is phenyl substituted with R or 2-pyridyl substituted with R; D is NH ₂ , NHCH ₃ , CH ₂ Selected from NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ , and C (CH ₃ ) ₂ NH ₂ , wherein D is substituted ortho to ring M on E; A compound wherein R is selected from H, OCH ₃ , Cl, and F. 5. The compound according to claim 4, wherein DE is 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, -Methoxy-2- (methylamino) phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-
2- (methylaminomethyl) phenyl, 4-methoxy-2- (1-aminoethyl) phenyl, 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-
Cl-2-aminophenyl, 4-Cl-2- (methylamino) phenyl, 4-C
l-2-aminomethylphenyl, 4-Cl-2- (methylaminomethyl) phenyl, 4-Cl-2- (1-aminoethyl) phenyl, 4-Cl-2- (2-amino-2-propyl) Phenyl, 4-F-2-aminophenyl, 4-F-2- (methylamino) phenyl, 4-F-2-aminomethylphenyl, 4-F-2- (methylaminomethyl) phenyl, 4-F- A compound selected from 2- (1-aminoethyl) phenyl and 4-F-2- (2-amino-2-propyl) phenyl. 6. The compound according to claim 3, wherein Z is C (O) CH ₂ and CONH, wherein Z does not form an NN bond with the group A; , phenyl, pyridyl, and is selected from pyrimidyl and substituted with 0-2 R ^4; B is, X-Y, phenyl, pyrrolidino, morpholino, selected 1,2,3-triazolyl, and imidazolyl, and substituted with 0-1 R ^4a; R ⁴ is in each _{case, OH, (CH 2) r} OR 2, halo, C _{1 ~ 4} alkyl, (C
_{^{H 2) r NR 2 R 2a}} , and (CF ₂₎ is selected from the _r CF _{3; R} ^4a is, C _{1 ~ 4 alkyl, CF 3, S (O)} p R 5, SO 2 NR 2 R 2a, and to R ⁵ are in each case, CF _3, C _{1 ~ 6} alkyl, selected from phenyl, and benzyl;; - 1 -CF ₃ is selected from tetrazol-2-yl X is CH ₂ or C (O) Y is selected from pyrrolidino and morpholino. 7. The compound according to claim 6, wherein A is a group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C
1-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2
- methylphenyl, selected 2-aminophenyl, and 2-methoxyphenyl; B is a group: 2-CF ₃ - phenyl, 2- (aminosulfonyl) phenyl, 2- (methylamino) phenyl, 2- ( Dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholino, 2- (1′-CF ₃ -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl -1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-methyl-1,2,3
-A compound selected from triazolyl. 8. The compound according to claim 3, wherein E is phenyl substituted with R or 2-pyridyl substituted with R; D is NH ₂ , NHCH ₃ , CH ₂ Selected from NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ , and C (CH ₃ ) ₂ NH ₂ , wherein D is substituted ortho to ring M on E; R is selected from H, OCH ₃ , Cl, and F; Z is C (O) CH ₂ and CONH, provided that Z does not form an N—N bond with group A; B is selected from XY, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0 to 2 R ⁴ ; substituted with ~ 1 amino R ^4a; R ^4, each field _{To, OH, (CH 2) r} OR 2, halo, C _{1 ~ 4} alkyl, (C
_{^{H 2) r NR 2 R 2a}} , and (CF ₂₎ is selected from the _r CF _{3; R} ^4a is, C _{1 ~ 4 alkyl, CF 3, S (O)} p R 5, SO 2 NR 2 R 2a, and to R ⁵ are in each case, CF _3, C _{1 ~ 6} alkyl, selected from phenyl, and benzyl;; - 1 -CF ₃ is selected from tetrazol-2-yl X is CH ₂ or C (O) Y is selected from pyrrolidino and morpholino. 9. The compound according to claim 8, wherein DE is 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, -Methoxy-2- (methylamino) phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-
2- (methylaminomethyl) phenyl, 4-methoxy-2- (1-aminoethyl) phenyl, 4-methoxy-2- (2-amino-2-propyl) phenyl, 4-
Cl-2-aminophenyl, 4-Cl-2- (methylamino) phenyl, 4-C
l-2-aminomethylphenyl, 4-Cl-2- (methylaminomethyl) phenyl, 4-Cl-2- (1-aminoethyl) phenyl, 4-Cl-2- (2-amino-2-propyl) Phenyl, 4-F-2-aminophenyl, 4-F-2- (methylamino) phenyl, 4-F-2-aminomethylphenyl, 4-F-2- (methylaminomethyl) phenyl, 4-F- A is selected from 2- (1-aminoethyl) phenyl, and 4-F-2- (2-amino-2-propyl) phenyl; A is a group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C
1-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2
- methylphenyl, selected 2-aminophenyl, and 2-methoxyphenyl; B is a group: 2-CF ₃ - phenyl, 2- (aminosulfonyl) phenyl, 2- (methylamino) phenyl, 2- ( Dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholino, 2- (1′-CF ₃ -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl -1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-methyl-1,2,3
-A compound selected from triazolyl. 10. The compound according to claim 9, wherein the compound is represented by the formula IIa. 11. The compound according to claim 9, wherein said compound is represented by formula IIb. 12. The compound according to claim 9, wherein said compound is represented by formula IIc. 13. The compound according to claim 9, wherein the compound is represented by formula IId. 14. The compound according to claim 9, wherein said compound is represented by formula IIe. 15. The compound according to claim 9, wherein the compound is represented by the formula IIf. 16. The compound of claim 3, wherein D is -CN, C (= NR⁸) NR⁷R⁹, C (O) NR⁷R⁸, NR⁷R⁸, And CH_TwoNR⁷R⁸Wherein D is ortho-substituted with respect to ring M on E; E is phenyl substituted with R or pyridyl substituted with R; R is H, Cl , F, OR^Three, CH_Three, CH_TwoCH_Three, OCF_Three, CF_Three, NR⁷R⁸ , And CH_TwoNR⁷R⁸Z is C (O), CH_TwoC (O), C (O) CH_Two, NHC (O), and C (
O) selected from NH, wherein Z does not form an NN bond with ring M or group A
R^1aAnd R^1bAre independently absent or-(CH_Two)_r-R^{1 '}, NCH_Two R^{1 "}, OCH_TwoR^{1 "}, SCH_TwoR^{1 "}, N (CH_Two)_Two(CH_Two)_tR^{1 '}, O (CH _Two )_Two(CH_Two)_tR^{1 '}, And S (CH_Two)_Two(CH_Two)_tR^{1 '}Is selected from
Or bond to form 0 to 2 R^Four5-8 membered, partially saturated, containing 0-2 heteroatoms selected from the group consisting of N, O, and S substituted with
Or an unsaturated ring; R^{1 '}Is, in each case, H, C_{1 ~ Three}Alkyl, halo, (CF_Two)_rCF_Three, OR ^Two , NR^TwoR^2a, C (O) R^2c, (CF_Two)_rCO_TwoR^2c, S (O)_pR^2b, NR^Two(CH_Two)_rOR^Two, NR^TwoC (O) R^2b, NR^TwoC (O)_TwoR^2b, C (O) NR^TwoR^2a , SO_TwoNR^TwoR^2a, And NR^TwoSO_TwoR^2bA is the following 0 to 2 R^FourCarbocyclic and heterocyclic ring systems substituted with: phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholini
Thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl
Thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl
B is Y, XY, NR^TwoR^2a, C (= NR^Two) NR^TwoR^2a, And NR^TwoC (=
NR^Two) NR^TwoR^2aX is CH_Two, -CR^Two(CR^TwoR^2b) (CH_Two)_t-, -C (O)-, -C (= NR)-, -CH (NR^TwoR^2a)-, -C (O) NR^Two-, -NR^TwoC (O)-, -NR^TwoC (O) NR^Two-, -NR^TwoAnd Y is NR^TwoR^2aWith the proviso that XY does not form an NN or ON bond; alternatively, Y is the next 0-2 R^FourCarbocyclic and heterocyclic ring systems substituted with: phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,
Morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isothio
Xazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl,
Imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3
-Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadia
Zolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2
1,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl
Ryl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-to
Razolyl, and one of 1,3,4-triazolyl; R^FourIs in each case ＝ O, OH, Cl, F, C_{1 ~ Four}Alkyl, (CH_Two)_r NR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, C (O) NR^TwoR^2a , CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^TwoR^2a, NR^TwoSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, And (CF_Two)_rCF_ThreeFrom
Selected; R^4aIs in each case ＝ O, OH, Cl, F, C_{1 ~ Four}Alkyl, (CH_Two)_r NR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, C (O) NR^TwoR^2a , CH (= NH) NH_Two, NHC (= NH) NH_Two, SO_TwoNR^TwoR^2a, NR^TwoSO_Two -C_{1 ~ Four}Alkyl, NR^TwoSO_TwoR^Five, S (O)_pR^Five, (CF_Two)_rCF_Three, And 1
-CF_Three-Tetrazol-2-yl; R^FiveIs, in each case, CF_Three, C_{1 ~ 6}Alkyl, 0-2 R⁶And 0 to 2 R⁶R selected from benzyl substituted with⁶Is, in each case, H, ＯO, OH, OR^Two, Cl, F, CH_Three, CN, NO_Two, (CH_Two)_rNR^TwoR^2a, (CH_Two)_rC (O) R^2b, NR^TwoC (O) R^2b, CH (= NH) NH_Two, NHC (= NH) NH_Two, And SO_TwoNR^TwoR^2aSelected from
R; R⁷Is in each case H, OH, C_{1 ~ 6}Alkyl, C_{1 ~ 6}Alkyl carbonyl, C_{1 ~ 6}Alkoxy, C_{1 ~ Four}Alkoxycarbonyl, benzyl, C_{6 ~ Ten}Aryloxy, C_{6 ~ Ten}Aryloxycarbonyl, C_{6 ~ Ten}Arylmethylcarbo
Nil, C_{1 ~ Four}Alkylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{6 ~ Ten} Arylcarbonyloxy C_{1 ~ Four}Alkoxycarbonyl, C_{1 ~ 6}Alkylamino
Carbonyl, phenylaminocarbonyl, and phenyl C_{1 ~ Four}Alkoxycal
Selected from Bonyl; R⁸Is, in each case, H, C_{1 ~ 6}Selected from alkyl and benzyl; alternatively, R⁷And R⁸Combine to form a morpholino group; R⁹Is, in each case, H, C_{1 ~ 6}A compound selected from alkyl and benzyl. 17. The compound according to claim 16, wherein E is phenyl substituted with R or 2-pyridyl substituted with R; R is H, Cl, F, OCH _3. , CH ₃ , OCF ₃ , CF ₃ , NH ₂ , and CH ₂ NH ₂ ; Z is selected from C (O) CH ₂ and C (O) NH, where Z is a group A and N- Does not form an N bond; R ^1a is H, CH ₃ , CH ₂ CH ₃ , Cl, F, CF ₃ , OCH ₃ , NR ² R ^2a , S
(O) _p R ^2b , CH ₂ S (O) _p R ^2b , CH ₂ NR ² S (O) _p R ^2b , C (O) R ² C, CH ₂ C (O) R ^2c , C (O) NR ² R ^2a , and SO ₂ NR ² R ^2a ; R ^1b is H, CH ₃ , CH ₂ CH ₃ , Cl, F, CF ₃ , OCH ₃ , NR ² R ^2a , S
(O) _p R ^2b , CH ₂ S (O) _p R ^2b , CH ₂ NR ² S (O) _p R ^2b , C (O) R ^2c ,
A is selected from CH ₂ C (O) R ^2c , C (O) NR ² R ^2a , and SO ₂ NR ² R ^2a ; A is a carbocyclic ring system substituted with 0 to 2 R ⁴ and Heterocyclic systems; phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl,
B is selected from one of isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from Y and XY; X is CH ₂ , —CR ² (CR ² R ^2b ) —, —C (O ) -, - C (= NR ) -, -CH (NR 2 R 2a) -, - C (O) NR 2 -, - NR 2 C (O) -, - NR 2 C (
^{O) NR 2 -, - NR} 2 -, and O is selected from; Y is NR ² R ^2a, provided that, X-Y do not form a N-N or O-N bond; or, Y is Carbocyclic and heterocyclic ring systems substituted with 0 to 2 R ^4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, Thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,2 3-thiadiazolyl, 1,2,4
-Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4- R ² is in each case selected from H, CF ₃ , CH ₃ , benzyl and phenyl; R ^2a is in each case H, CF ₃ , CH ₃ R ^2b is in each case selected from CF ₃ , OCH ₃ , CH ₃ , benzyl and phenyl; R ^2c is in each case CF ₃ , OH, OCH containing Alternatively, R ² and R ^2a are bonded, N, O, and 0-1 additional heteroatoms selected from the group consisting of S; _3, CH _3, benzyl, and is selected from the off Eniru 5 or 6-membered saturated, partially unsaturated or unsaturated ring; R ³ is in each case selected from H, CH ₃ , CH ₂ CH ₃ and phenyl; R ^3a is in each case: R is selected from H, CH ₃ , CH ₂ CH ₃ , and phenyl; R ⁴ is in each case OH, Cl, F, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , and CF ₃ ; R ^4a is in each case OH, Cl, F, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , C
_{^{H 2 NR 2 R 2a, C}} (O) R 2b, C (O) NR 2 R 2a, SO 2 NR 2 R 2a, S (O) p R 5, CF 3, and 1-CF ₃ - tetrazol -2 - is selected from-yl; R ⁵ is selected in each case, CF _3, C _{1 ~ 6} alkyl, phenyl substituted with 0-2 R ^6, and from one benzylidene substituted with R ⁶ R ⁶ is in each case H, OH, OCH ₃ , Cl, F, CH ₃ , CN, NO ₂ ,
_{^{NR 2 R 2a, CH 2 NR}} 2 R 2a, and SO ^₂ NR ₂ R ^2a is selected from; R ⁷ are in each case selected from H and C _{1 ~ 3} alkyl; R ⁸ is in each case to, H, CH _3, and is selected from benzyl; R ⁹ is in each case H, is selected from CH _3, and benzyl; t are in each case is selected from 0 and 1, it A compound characterized by the following. 18. The compound of claim 17, wherein D is NR⁷R⁸, And CH_TwoNR⁷R⁸Wherein D is substituted ortho to ring M on E;^1aIs absent or H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH _Three , NR^TwoR^2a, S (O)_pR^2b, C (O) NR^TwoR^2a, CH_TwoS (O)_pR^2b, CH _Two NR^TwoS (O)_pR^2b, C (O) R^2c, CH_TwoC (O) R^TwoC and SO_TwoNR^Two R^2aSelected from; R^1bIs absent or H, CH_Three, CH_TwoCH_Three, Cl, F, CF_Three, OCH _Three , NR^TwoR^2a, S (O)_pR^2b, C (O) NR^TwoR^2a, CH_TwoS (O)_pR^2b, CH _Two NR^TwoS (O)_pR^2b, C (O) R^2b, CH_TwoC (O) R^2b, And SO_TwoNR^TwoR ^2a A is the following 0 to 2 R^FourB is selected from Y and XY; X is selected from -C (O)-and O Y is NR^TwoR^2aWith the proviso that XY does not form an ON bond; or Y is 0-2 R^4aCarbocyclic and heterocyclic ring systems substituted with
Nil, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, i
R is selected from midazolyl, and one of 1,2,3-triazolyl; R^TwoIs, in each case, H, CF_Three, CH_ThreeR, benzyl, and phenyl;^2aIs, in each case, H, CF_Three, CH_Three, Benzyl, and phenyl
Selected; R^2bIs, in each case, CF_Three, OCH_Three, CH_ThreeR, benzyl, and phenyl; R^2cIs, in each case, CF_Three, OH, OCH_Three, CH_Three, Benzyl, and phenyl;^TwoAnd R^2aCombine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino; R^FourIs, in each case, Cl, F, CH_Three, NR^TwoR^2aAnd CF_ThreeSelected from
R^4aIs, in each case, Cl, F, CH_Three, SO_TwoNR^TwoR^2a, S (O)_pR^Five, And CF_ThreeSelected from; R^FiveIs, in each case, CF_ThreeAnd CH_ThreeSelected from; R⁷Is, in each case, H, CH_Three, And CH_TwoCH_ThreeSelected from; R⁸Is in each case H and CH_ThreeA compound selected from the group consisting of: 19. The compound according to claim 1, which is selected from the following: and a pharmaceutically acceptable salt thereof: 3-methyl-1- (2-aminomethyl-4 -Methoxyphenyl) -1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4 -Methoxyphenyl) -1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl -4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxy) Phenyl)-
1H-pyrazole-5- (N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl) -1H-pyrazole-5- (N- (2'-sulfamide- [1,1 '
] -Bifen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 '] -Bifene-4-
Yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2′-methylsulfonyl- [1,1 ′]-biphen-4) −
Yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,
1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide -[1,1 ']-biphen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-sulfamide- [1,1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- ( 3-fluoro-2'-methylsulfonyl- [1,1 ']-
Bifen-4-yl)) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1 , 1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ′]-Bifen-4-yl)) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole 5- (N- (3-fluoro-2′-methylsulfonyl- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro -2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N -(4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (1-pyrroli Dinocarbonyl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl)
Carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl)
Carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl- 1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (2-fluoro-4- (1-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5 -(N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N -(5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoate) Xyphenyl)
-1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) ) -1H-Pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridine-2)
-Yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methylsulfonyl) phenyl) pyridine-2-
Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl)
Pyridin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxy Phenyl) -1H-pyrazole-5- (N- (5-((2-methylsulfonyl)
Phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidine -2-
Yl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidine-2-
Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyrimidin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-sulfamide) phenyl) pyrimidin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl ) -1H-Pyrazole-5- (N- (5-((2-sulfamido) phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H -Pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidine-
2-ethyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methylsulfonyl) phenyl) pyrimidine-2
-Yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl)
Pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidin-2-yl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) −
1H-pyrazole-5- (N- (5-((2-methylsulfonyl) phenyl) pyrimidin-2-yl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxy Phenyl) -1H-pyrazole-5- (N- (5-((2-methylsulfonyl)
Phenyl) pyrimidin-2-yl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1) -Yl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) Phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl)
Phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl) ) -1H-Pyrazole-5- (N- (4-((2-methyl) imidazo-
1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazol-5- (N- (4-((5-methyl) imidazo-1-yl ) Phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) Carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl)
Phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl)-
1H-pyrazole-5- (N- (4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl-4-methoxyphenyl ) -1H-Pyrazole-5- (N- (4-((5-methyl) imidazo-
1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo -1-yl) phenyl) carboxamide; 3-ethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) Imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((2-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-aminomethyl -4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-amino Methyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoro L-methyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-methyl-1- (2-N-methylaminomethyl-4 -Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-ethyl-1- (2-N-methylaminomethyl-4- Methoxyphenyl)-
1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide; 3-trifluoromethyl-1- (2-N-methylaminomethyl- 4-Methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-((5-methyl) imidazo-1-yl) phenyl) carboxamide. 20. The compound according to claim 1, which is selected from: 3-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5 -(N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 5-methyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-3 -(N- (2'-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-methyl-1- (2-N, N-dimethylaminomethyl-4-methoxyphenyl)- 1H-pyrazole-5- (N- (2′-N-methylsulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (2'-methylsulfonyl- [1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxy Phenyl)
-1H-pyrazole-5- (N- (2'-sulfamide- [1,1] -biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) )
-1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl)
Carboxamide; N-benzylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5-carboxamide)
Piperidine; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5- (2'-sulfonamido) phenyl) pyrid-2-yl) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl)
-1H-pyrazole-5- (N- (5- (pyrid-2-yl)) pyrid-2-yl) carboxamide; N-benzyl-4- (3-trifluoromethyl-1- (2-aminomethyl -4
-Methoxyphenyl) -1H-pyrazole-5-carboxamido) piperidine; N-phenylsulfonyl-4- (3-trifluoromethyl-1- (2-aminomethyl-4-methoxyphenyl) -1H-pyrazole-5 Carboxamido) piperidine; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ']-Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1
, 1 ']-Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-chlorophenyl)-
1H-pyrazole-5- (N- (3-fluoro-2′-sulfamide- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-5-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5- (N- (3-fluoro- 2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4,5-difluorophenyl) -1H-pyrazole-5 -(N- (3-fluoro-2'-sulfamide-
[1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [
1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-3-fluorophenyl)
-1H-pyrazole-5- (N- (3-fluoro-2'-sulfamide- [1,
1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (2-methylsulfonyl- [1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-fluorophenyl)
-1H-pyrazole-5- (N- (4- (2-sulfamide- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4 -Fluorophenyl)
-1H-pyrazole-5- (N- (4- (N-((N'-methylsulfonyl) iminoyl) pyrrolidino)) phenyl) carboxamide; 3-trifluoromethyl-1- (2- (N-glycyl) Aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoro Methyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2
'-Methylsulfonyl- [1,1']-biphen-4-yl)) carboxamide; 3- (trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H-
Pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-
4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]-biphene) -4
-Yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-aminosulfonyl- [1,1 ' ]
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [ 1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N- (glycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ' -Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-((N- (N-methylglycyl) aminomethyl) phenyl) -1H-pyrazole -5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-carboxamidophenyl) -1H -Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-cyanophenyl) -1H-pyrazole-
5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 1- (2'-aminomethylphenyl) -5-[[(2 '-Methylsulfonyl)
-3-fluoro- [1,1 ']-biphen-4-yl] aminocarbonyl] -tetrazole; 1- (2'-aminomethylphenyl) -5-[(2'-aminosulfonyl- [
1,1 ′]-biphen-4-yl) aminocarbonyl] -tetrazole; 1- [2- (aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)- (2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorophenyl) -1H-pyrazole-5- ( N- (4- (2-methylsulfonyl- [1,1
'] -Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorofluorophenyl) -1H-pyrazole-5- (N- (4- (2- Sulfamide- [1,1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl-4-trifluorophenyl) -1H-pyrazole-5- (N- (N'-methylsulfonyl) iminoyl )
Pyrrolidino)) phenyl) carboxamide; 3-trifluoromethyl-1- (2- (N-glycyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-2′- Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N-phenylacetyl) aminomethyl-4-methoxyphenyl) -1H-pyrazole- 5- (N- (3-fluoro-2
'-Aminosulfonyl- [1,1']-biphen-4-yl)) carboxamide; 3- (trifluoromethyl) -1- (2- (aminomethyl) phenyl) -1H
-Pyrazole-5- (N- (2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl)- 1H-pyrazole-5- (N- (2′-aminosulfonyl- [1,1 ′]-biphen-4
-Yl)) carboxamide; 3-trifluoromethyl-1- (2-aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2'-aminosulfonyl- [1,1 '] −
Bifen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2′-methylsulfonyl- [1 , 1 ']
-Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2- (N- (glycyl) aminomethyl) phenyl) -1H-pyrazole-5- (N- (3-fluoro-2 ' -Methylsulfonyl- [1,1 ′]-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-((N- (N-methylglycyl) aminomethyl) phenyl) -1H-pyrazole -5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-carboxamidophenyl) -1H -Pyrazole-5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-
Biphen-4-yl)) carboxamide; 3-trifluoromethyl-1- (2-cyanophenyl) -1H-pyrazole-
5- (N- (3-fluoro-2'-methylsulfonyl- [1,1 ']-biphen-4-yl)) carboxamide; 1- (2'-aminomethylphenyl) -5-[[(2 '-Methylsulfonyl)
-3-fluoro- [1,1 ']-biphen-4-yl] aminocarbonyl] -tetrazole; 1- (2'-aminomethylphenyl) -5-[(2'-methylsulfonyl)-
[1,1 ′]-biphen-4-yl] aminocarbonyl] -tetrazole; 1- [2- (aminomethyl) phenyl] -3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl) -[1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-methylsulfonyl-5-[(2
-Fluoro)-(2'-methylsulfonyl- [1,1 ']-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)- (2'-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] triazole; 1- [2- (aminomethyl) phenyl] -5-[(2-fluoro)-(2′-
Methylsulfonyl- [1,1 ′]-biphen-4-yl) aminocarbonyl] pyrazole; 1- [2- (aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2′-pyrrolidinomethyl)-[1,1 ′]-biphen-4
-Yl) aminocarbonyl] pyrazole; and 1- [2- (aminomethyl) phenyl] -3-trifluoromethyl-5-[(
(2-Fluoro)-(2′-hydroxymethyl)-[1,1 ′]-biphen-4
-Yl) aminocarbonyl] pyrazole. 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. 22. A method for treating or preventing a thromboembolic disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. A method comprising administering